Feline IL-12 single chain proteins and nucleic acid molecules

ABSTRACT

The present invention relates to canine and feline proteins. In particular, the present invention discloses feline interleukin-18, feline caspase-1, feline interleukin-12 single chain and canine interleukin-12 single chain proteins. The present invention also includes feline interleukin-18, feline caspase-1, feline interleukin-12 single chain and canine interleukin-12 single chain nucleic acid molecules encoding such proteins, antibodies raised against such proteins and/or inhibitors of such proteins or nucleic acid molecules. The present invention also includes therapeutic compositions comprising such nucleic acid molecules, proteins, antibodies and/or inhibitors, as well as their use to evaluate and regulate an immune response in an animal.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/223,016, which was filed Aug. 4, 2000, entitled “CANINEAND FELINE PROTEINS, NUCLEIC ACID MOLECULES AND USES THEREOF”.

FIELD OF THE INVENTION

[0002] The present invention relates to canine and feline proteins. Inparticular, the present invention relates to feline interleukin-18(IL-18), feline caspase-1 (casp-1), feline interleukin-12 (IL-12) singlechain, and canine interleukin-12 (IL-12) single chain proteins andincludes nucleic acid molecules encoding such proteins, antibodiesraised against such proteins and/or inhibitors of such proteins ornucleic acid molecules. The present invention also includes therapeuticcompositions comprising such nucleic acid molecules, proteins,antibodies and/or inhibitors, as well as their use to evaluate andregulate an immune response in an animal.

BACKGROUND OF THE INVENTION

[0003] Regulation of immune and inflammatory responses in animals isimportant in disease management. Immune responses can be regulated bymodifying the activity of immunoregulatory molecules and immune cells.Examples of such immunoregulatory molecules include IL-18, caspase-1 andIL-12. These molecules have been found to play a role in the treatmentof several disorders including allergy, cancer, and pathogenicinfection.

[0004] Monocytes and macrophages represent the first line of defenseagainst disease. Various diseases and infections activatetranscriptional and posttranslational events in monocytes andmacrophages, which lead to the production of cytokines such as IL-18 andIL-12. These cytokines in turn activate responses in T and B cellshelping to eliminate pathogens and/or disease in a animal. Both IL-18and IL-12 augment cellular immunity by stimulating T cells to produceinterferon gamma (IFN-γ) which inhibits the production of IgE formationwithout compromising B cell proliferation. IL-18, formerly referred toas interferon gamma inducing factor (IGIF), stimulates T cells toproduce IFN-γ and has been isolated from humans, dogs, and mice. A cDNAencoding human IL-18 was isolated and used to express recombinant humanIL-18 by Ushio et al., 1996, J. Immunol.156, 4274-4279, GenBankaccession number D49950. Feline IL-18 cDNA has a 85.8% homology to humanIL-18 cDNA and feline IL-18 protein has a 81.7% homology to human IL-18protein. A cDNA encoding canine IL-18 was isolated and used to expressrecombinant canine IL-18 by Okano et al., 1999, J. Interferon CytokineRes. 19, 27-32, GenBank accession number Y11133. Feline IL-18 cDNA has a90.7% homology to canine IL-18 cDNA and feline IL-18 protein has a 88.5%homology to canine IL-18 protein. A cDNA encoding murine IL-18 wasisolated and used to express recombinant murine IL-18 by Okamura et al.,1995, Nature 378, 88-91, GenBank accession number D49949. Feline IL-18cDNA has a 73.8% homology to murine IL-18 cDNA and feline IL-18 proteinhas a 70% homology to murine IL-18 protein. A cDNA encoding rat IL-18was isolated by Culhane, et al. Mol. Psych. 3, 362-366 (1998), GenBankaccession number AJ222813. Feline IL-18 cDNA has a 73.4% homology withrat IL-18 cDNA, and feline IL-18 protein has a 70.7% homology with ratIL-18 protein. A cDNA encoding equine IL-18 was isolated by Nicolson, etal. (unpublished, direct submission to GenBank, accession numberY11131). Feline IL-18 cDNA has a 92% homology to equine IL-18 cDNA andfeline IL-18 protein has a 89% homology to equine IL-18 protein. A cDNAencoding pig IL-18 was isolated by Penha-Goncalves, et al. (unpublished,direct submission to GenBank, accession number Y11132. Feline IL-18 cDNAhas a 90.2% homology to pig IL-18 cDNA and feline IL-18 protein has a85.9% homology to pig IL-18 protein. Expression of active IL-18 iscontrolled by caspase-1(IL-lβ converting enzyme). That is, IL-18 lacks asignal peptide so the precursor form of IL-18 (pro IL-18) is cleaved bycaspase-1 resulting in a mature protein that is biologically active.

[0005] IL-12 is a heterodimer comprised of two subunits p40 and p35which are covalently linked by a disulfide bond to form an activemolecule. Simultaneous expression of the two subunits is necessary forthe production of the biologically active heterodimer. Both human andmurine p35 and p40 IL-12 single chain proteins (i.e., a single proteincontaining both p35 and p40 subunits) have been produced; see e.g.,Lieschke et al., 1997, Nature Biotechnology 15, 35-40. Co-expression ofthe human and murine p35 and p40 cDNA subunits of IL-12 resulting in abiologically active IL-12 heterodimer was achieved by Gubler et al.,1991, Proc. Natl. Acad. Sci. U.S.A., 88, 4143-4147 and Schoenhaut etal., 1992, J. Immunol., 148, 3433-3440, respectively. cDNAs encodingcanine IL-12 p35 and p40 subunits were isolated and co-transfected toexpress canine IL-12 by Okano et al., 1997, J. Interferon Cytokine Res.17, 713-718. cDNAs encoding feline p35 and p40 subunits have beenisolated and expressed; see, for example, Fehr et al., 1997, DNA Seq. 8,77-82; Schijns et al., 1997, Immunogenetics 45, 462-463; Bush et al.,1994, Molec. Immunol. 31, 1373-1374. At the amino acid level, canine andfeline IL-12 p40 subunit share 92.7 percent identity to each other;share 84.8 and 84.2 percent identity to human IL-12 p40, respectively;and share 67.4 and 68.9 percent identity to murine IL-12 p40,respectively. IL-12 shares some biological activities with IL-18including IFN-γ production in T cells. IL-18 and IL-12 in combinationwork synergistically to increase IFN-γ production in T cells; as suchthese cytokines when utilized alone or in combination can be veryeffective in mediating IgE responses.

[0006] Caspase-1 may play a key role in the processing of IL-18precursor in cells where IL-18 is produced. It may be that coexpressionof caspase-1 along with IL-18 may be necessary for the proper processingof the IL-18 precursor and enhanced secretion of the processed IL-18mature polypeptide. A cDNA encoding equine caspase-1 was isolated byWardlow, et al. (unpublished; direct submission to GenBank, accessionnumber AF090119). Feline caspase-1 cDNA has a 71% homology to equinecaspase-1 cDNA and feline caspase-1 protein has a 48.8% homology toequine caspase-1 protein. A cDNA encoding equine caspase-1 was isolatedby Cerretti, et al. (Science 256, p 97-100 (1992); GenBank accessionnumber M87507). Feline caspase-1 cDNA has a 60% homology to humancaspase-1 cDNA and feline caspase-1 protein has a 60% homology to humancaspase-1 protein. A cDNA encoding rat caspase-1 (called interleukin-1beta converting enzyme) was isolated by Keane, et al. (Cytokine 7(2)105-110 1995); GenBank accession number U14647). Feline caspase-1 cDNAhas a 55.4% homology to rat caspase-1 cDNA and feline caspase-1 proteinhas a 40.2% homology to rat caspase-1 protein. A cDNA encoding murinecaspase-1 was isolated by Molineaux, et al. (Proc Natl. Acad. Sci 90,1809-1813, 1993); GenBank accession number L28095). Feline caspase-1cDNA has a 55.7% homology to murine caspase-1 cDNA and feline caspase-1protein has a 38.5% homology to murine caspase-1 protein. A cDNAencoding canine caspase-1 was isolated by Taylor, et al. (2000) DNA Seq.10(6), pp 387-394; GenBank accession number AF135967). Feline caspase-1cDNA has a 90% homology to canine caspase-1 cDNA.

[0007] To date, however, neither IL-18 nor caspase-1, nor the nucleicacid molecules encoding such proteins, have been isolated from cats.Neither have IL-12 single chain proteins been produced using feline orcanine IL-12 subunits. As such there remains a need for compounds andmethods to regulate an immune response in cats and dogs throughmanipulation of IL-18, caspase-1 and IL-12 single chain activities.

SUMMARY OF THE INVENTION

[0008] The present invention relates to canine and feline proteins,nucleic acid molecules encoding such proteins, antibodies raised againstsuch proteins and/or inhibitors of such proteins or nucleic acidmolecules. In a preferred embodiment, the present invention relates tofeline interleukin-18 (IL-18), feline caspase-1 (casp-1), felineinterleukin-12 (IL-12) single chain and canine interleukin-12 singlechain proteins, nucleic acid molecules, antibodies and inhibitors. Thepresent invention also includes therapeutic compositions comprising suchnucleic acid molecules, proteins, antibodies and/or inhibitors, as wellas their use to evaluate and regulate an immune response in an animal.

[0009] One embodiment of the present invention is an isolated nucleicacid molecule selected from the group consisting of: (a) an isolatednucleic acid molecule selected from the group consisting of (i) anucleic acid molecule comprising a nucleic acid sequence selected fromthe group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:6, SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:9, SEQ ID NO:41, SEQ IDNO:11, and SEQ ID NO:13; and (ii) a nucleic acid molecule comprising atleast 70 contiguous nucleotides identical in sequence to at least 70contiguous nucleotides of a nucleic acid sequence selected from thegroup consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6,SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:13, andSEQ ID NO:41; (b) an isolated nucleic acid molecule selected from thegroup consisting of (i) a nucleic acid molecule comprising a nucleicacid sequence selected from the group consisting of SEQ ID NO:14, SEQ IDNO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ IDNO:23 and SEQ ID NO:25, and (ii) a nucleic acid molecule comprising atleast 70 contiguous nucleotides identical in sequence to at least 70contiguous nucleotides of a nucleic acid sequence selected from thegroup consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:17, SEQ IDNO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:25; (c) anisolated nucleic acid molecule selected from the group consisting of:(i) a nucleic acid molecule comprising ((a)) an isolated nucleic acidmolecule comprising a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:26, SEQ ID NO:29, and a nucleic acid sequencecomprising at least 44 contiguous nucleotides identical in sequence toat least 44 contiguous nucleotides of a nucleic acid sequence selectedfrom the group consisting of SEQ ID NO:26 and SEQ ID NO:29; ((b)) anucleic acid linker of (XXX)_(n) wherein n=0 to 60; and ((c)) anisolated nucleic acid molecule comprising a nucleic acid sequenceselected from the group consisting of SEQ ID NO:32, SEQ ID NO:35, and anucleic acid molecule comprising at least 44 contiguous nucleotidesidentical in sequence to at least 44 contiguous nucleotides of a nucleicacid sequence selected from the group consisting of SEQ ID NO:32 and SEQID NO:35, such that said nucleic acid molecule of (i) encodes a felineIL-12 single chain protein; and (ii) a nucleic acid molecule comprisinga nucleic acid sequence fully complementary to the coding strand of anyof said nucleic acid molecules as set forth in (i); (d) an isolatednucleic acid molecule selected from the group consisting of: (i) anucleic acid molecule comprising ((a)) an isolated nucleic acid moleculecomprising a nucleic acid sequence selected from the group consisting ofSEQ ID NO:52 and SEQ ID NO:58, and a nucleic acid sequence comprising atleast 47 contiguous nucleotides identical in sequence to at least 47contiguous nucleotides of a nucleic acid sequence selected from thegroup consisting of SEQ ID NO:46 and SEQ ID NO:49; ((b)) a nucleic acidlinker of (XXX)_(n) wherein n=0 to 60; and ((c)) an isolated nucleicacid molecule comprising a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:46, SEQ ID NO:49, and a nucleic acid moleculecomprising at least 47 contiguous nucleotides identical in sequence toat least 47 contiguous nucleotides of a nucleic acid sequence selectedfrom the group consisting of SEQ ID NO:46 and SEQ ID NO:49, such thatsaid nucleic acid molecule of (i) encodes a canine IL-12 single chainprotein; and (ii) a nucleic acid molecule comprising a nucleic acidsequence fully complementary to the coding strand of any of said nucleicacid molecules as set forth in (i); (e) an isolated nucleic acidmolecule selected from the group consisting of: (i) a nucleic acidmolecule having a nucleic acid sequence that is at least 92 percentidentical to a nucleic acid sequence selected from the group consistingof SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQID NO:10, SEQ ID NO:9, SEQ ID NO:41, SEQ ID NO:11, and SEQ ID NO:13; and(ii) a nucleic acid molecule comprising a fragment of a nucleic acidmolecule of (i) wherein said fragment is at least 80 nucleotides inlength; (f) an isolated nucleic acid molecule selected from the groupconsisting of (i) a nucleic acid molecule having a nucleic acid sequencethat is at least 85 percent identical to a nucleic acid sequenceselected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ IDNO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23 and SEQ IDNO:25, and (ii) a nucleic acid molecule comprising a fragment of anucleic acid molecule of (i) wherein said fragment is at least 85nucleotides in length; (g) an isolated nucleic acid molecule selectedfrom the group consisting of: (i) a nucleic acid molecule comprising((a)) a nucleic acid molecule comprising a nucleic acid sequence that isat least 87 percent identical to a nucleic acid sequence selected fromthe group consisting of SEQ ID NO:26 and SEQ ID NO:29, or a fragmentthereof of at least 55 nucleotides in length; ((b)) a nucleic acidlinker of (XXX)_(n) wherein n=0 to 60; and ((c)) nucleic acid moleculecomprising a nucleic acid sequence that is at least 87 percent identicalto a nucleic acid sequence selected from the group consisting of SEQ IDNO:32 and SEQ ID NO:35, or a fragment thereof of at least 55 nucleotidesin length, such that said nucleic acid molecule (i) encodes a felineIL-12 single chain protein; and (ii) a nucleic acid molecule comprisinga nucleic acid sequence fully complementary to the coding strand of anucleic acid molecule as set forth in (i); and (h) an isolated nucleicacid molecule selected from the group consisting of: (i) a nucleic acidmolecule comprising ((a)) an isolated nucleic acid molecule comprising anucleic acid sequence selected from the group consisting of SEQ ID NO:52and SEQ ID NO:58, and a nucleic acid sequence comprising at least 55contiguous nucleotides identical in sequence to at least 55 contiguousnucleotides of a nucleic acid sequence selected from the groupconsisting of NO:52 and SEQ ID NO:58; ((b)) a nucleic acid linker of(XXX)_(n) wherein n=0 to 60; and ((c)) an isolated nucleic acid moleculecomprising a nucleic acid sequence selected from the group consisting ofSEQ ID NO:46, SEQ ID NO:49, and a nucleic acid molecule comprising atleast 55 contiguous nucleotides identical in sequence to at least 55contiguous nucleotides of a nucleic acid sequence selected from thegroup consisting of SEQ ID NO:32 and SEQ ID NO:35, such that saidnucleic acid molecule of (i) encodes a canine IL-12 single chainprotein; and (ii) a nucleic acid molecule comprising a nucleic acidsequence fully The present invention also includes recombinantmolecules, recombinant viruses and recombinant cells comprising suchIL-18, caspase-1, and IL-12 single chain nucleic acid molecules andmethods to produce such nucleic acid molecules, recombinant molecules,recombinant viruses and recombinant cells.

[0010] Another embodiment of the present invention is an isolatednucleic acid molecule selected from the group consisting of: (a) anucleic acid molecule having a nucleic acid sequence encoding an IL-18protein selected from the group consisting of: (i) a protein selectedfrom the group consisting of ((a)) a protein having an amino acidsequence that is at least 92 percent identical to an amino acid sequenceselected from the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8 and SEQ ID NO:12, and ((b)) a protein comprising a fragment of aprotein of ((a)), wherein said fragment is at least 30 amino acids inlength; and (ii) a protein comprising at least 25 contiguous amino acidsidentical in sequence to at least 25 contiguous amino acids of an aminoacid sequence selected from the group consisting of SEQ ID NO:2, SEQ IDNO:5, SEQ ID NO:8 and SEQ ID NO:12; (b) a nucleic acid molecule having anucleic acid sequence encoding a caspase-1 protein selected from thegroup consisting of: (i) a protein selected from the group consisting of((a)) a protein having an amino acid sequence that is at least 85percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ IDNO:24, and ((b)) a protein comprising a fragment of a protein of ((a)),wherein said fragment is at least 30 amino acids in length; and (ii) aprotein comprising at least 25 contiguous amino acids identical insequence to at least 25 contiguous amino acids selected from the groupconsisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ IDNO:24; (c) a nucleic acid molecule having a nucleic acid sequenceencoding an IL-12 single chain protein comprising an IL-12 p40 subunitdomain linked to a IL-12 p35 subunit domain, wherein said p40 subunitdomain is selected from the group consisting of (i) a p40 subunitprotein having an amino acid sequence that is at least 84 percentidentical to an amino acid sequence selected from the group consistingof SEQ ID NO:27 and SEQ ID NO:30, (ii) a p40 subunit protein comprisinga fragment of a protein of (i), wherein said fragment is at least 30amino acids in length, and (iii) a p40 subunit protein comprising atleast 23 contiguous amino acids identical in sequence to at least 23contiguous amino acids of an amino acid sequence selected from the groupconsisting of SEQ ID NO:27 and SEQ ID NO:30 and wherein said p35 subunitdomain is selected from the group consisting of (i) a p35 subunitprotein having an amino acid sequence that is at least 84 percentidentical to an amino acid sequence selected from the group consistingof SEQ ID NO:33 and SEQ ID NO:36, (ii) a p35 subunit protein comprisinga fragment of a protein of (i), wherein said fragment is at least 30amino acids in length, and (iii) a p35 subunit protein comprising atleast 23 contiguous amino acids identical in sequence to at least 23contiguous amino acids of an amino acid sequence selected from the groupconsisting of SEQ ID NO:33 and SEQ ID NO:36; (d) a nucleic acid moleculehaving a nucleic acid sequence encoding an IL-12 single chain proteincomprising an IL-12 p40 subunit domain linked to a IL-12 p35 subunitdomain, wherein said p40 subunit domain is selected from the groupconsisting of (i) a p40 subunit protein having an amino acid sequencethat is at least 84 percent identical to an amino acid sequence selectedfrom the group consisting of SEQ ID NO:53 and SEQ ID NO:59, (ii) a p40subunit protein comprising a fragment of a protein of (i), wherein saidfragment is at least 40 amino acids in length, and (iii) a p40 subunitprotein comprising at least 31 contiguous amino acids identical insequence to at least 31 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:53 and SEQ ID NO:59, andwherein said p35 subunit domain is selected from the group consisting of(i) a p35 subunit protein having an amino acid sequence that is at least84 percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:47 and SEQ ID NO:50, (ii) a p35 subunit proteincomprising a fragment of a protein of (i), wherein said fragment is atleast 40 amino acids in length, and (iii) a p35 subunit proteincomprising at least 31 contiguous amino acids identical in sequence toat least 31 contiguous amino acids of an amino acid sequence selectedfrom the group consisting of SEQ ID NO:47 and SEQ ID NO:50; (e) anucleic acid molecule comprising a nucleic acid sequence fullycomplementary to the coding strand of any of said nucleic acid moleculesas set forth in (a), (b), (c), or (d). The present invention alsoincludes recombinant molecules, recombinant viruses and recombinantcells comprising such IL-18, caspase-1, and IL-12 single chain nucleicacid molecules and methods to produce such nucleic acid molecules,recombinant molecules, recombinant viruses and recombinant cells.

[0011] Another embodiment of the present invention is an isolatedprotein selected from the group consisting of: (a) an isolated IL-18protein selected from the group consisting of: (i) an isolated proteinof at least 25 amino acids in length, wherein said protein has an atleast 25 contiguous amino acid region identical in sequence to a 25contiguous amino acid region selected from the group consisting of SEQID NO:2, SEQ ID NO:5, SEQ ID NO:8 and SEQ ID NO:12; and (ii) an isolatedprotein having an amino acid sequence that is at least 92 percentidentical to an amino acid sequence selected from the group consistingof SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8 and SEQ ID NO:12 and a fragmentthereof of at least 30 nucleotides; wherein said isolated protein has afunction selected from the group consisting of (i) eliciting an immuneresponse against an IL-18 protein having an amino acid sequence selectedfrom the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8 andSEQ ID NO:12, (ii) selectively binding to an antibody raised against anIL-18 protein having an amino acid sequence selected from the groupconsisting of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ ID NO:12,and (iii) exhibiting IL-18 activity; (b) an isolated caspase-1 proteinselected from the group consisting of: (i) an isolated protein of atleast about 25 amino acids in length, wherein said protein has an atleast 25 contiguous amino acid region identical in sequence to a 25contiguous amino acid region selected from the group consisting of SEQID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24; and (ii) anisolated protein having an amino acid sequence that is at least 85percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24and has a nucleic acid fragment thereof of at least 30 nucleotides;wherein said isolated protein has a function selected from the groupconsisting of (i) eliciting an immune response against a caspase-1protein having an amino acid sequence selected from the group consistingof SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24, (ii) ii)selectively binding to an antibody raised against caspase-1 proteinhaving an amino acid sequence selected from the group consisting of SEQID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24, and (iii)exhibiting caspase-1 activity; (c) an isolated IL-12 single chainprotein comprising an IL-12 p40 subunit domain linked to an IL-12 p35subunit domain, wherein said p40 subunit domain is selected from thegroup consisting of (i) a p40 subunit protein having an amino acidsequence that is at least 84 percent identical to an amino acid sequenceselected from the group consisting of SEQ ID NO:27 and SEQ ID NO:30,(ii) a p40 subunit protein comprising a fragment of a protein of (i),wherein said fragment is at least 30 amino acids in length, and (iii) ap40 subunit protein comprising at least 23 contiguous amino acidsidentical in sequence to at least 23 contiguous amino acids of an aminoacid sequence selected from the group consisting of SEQ ID NO:27 and SEQID NO:30 and wherein said p35 subunit domain is selected from the groupconsisting of (i) a p35 subunit protein having an amino acid sequencethat is at least 84 percent identical to an amino acid sequence selectedfrom the group consisting of SEQ ID NO:33 and SEQ ID NO:36, (ii) a p35subunit protein comprising a fragment of a protein of (i), wherein saidfragment is at least 30 amino acids in length, and (iii) a p35 subunitprotein comprising at least 23 contiguous amino acids identical insequence to at least 23 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:33 and SEQ ID NO:36;wherein said isolated protein has a function selected from the groupconsisting of (i) eliciting an immune response against an IL-12 proteinhaving an amino acid sequence selected from the group consisting of SEQID NO:39 and SEQ ID NO:44, (ii) selectively binding to an antibodyraised against an IL-12 protein having an amino acid sequence selectedfrom the group consisting of SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33,SEQ ID NO:36, SEQ ID NO:47, SEQ ID NO:50, SEQ ID NO:53, and SEQ IDNO:59, SEQ ID NO:102, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:39, SEQ IDNO:40, SEQ ID NO:62, and/or SEQ ID NO:67, and (iii) exhibiting IL-12activity; and (d) an isolated IL-12 single chain protein comprising anIL-12 p40 subunit domain linked to an IL-12 p35 subunit domain, whereinsaid p40 subunit domain is selected from the group consisting of (i) ap40 subunit protein having an amino acid sequence that is at least 84percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:53 and SEQ ID NO:59, (ii) a p40 subunit proteincomprising a fragment of a protein of (i), wherein said fragment is atleast 40 amino acids in length, and (iii) a p40 subunit proteincomprising at least 31 contiguous amino acids identical in sequence toat least 31 contiguous amino acids of an amino acid sequence selectedfrom the group consisting of SEQ ID NO:53 and SEQ ID NO:59; wherein saidp35 subunit domain is selected from the group consisting of (i) a p35subunit protein having an amino acid sequence that is at least 84percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:47 and SEQ ID NO:50, (ii) a p35 subunit proteincomprising a fragment of a protein of (i), wherein said fragment is atleast 40 amino acids in length, and (iii) a p35 subunit proteincomprising at least 31 contiguous amino acids identical in sequence toat least 31 contiguous amino acids of an amino acid sequence selectedfrom the group consisting of SEQ ID NO:47 and SEQ ID NO:50; and whereinsaid isolated protein has a function selected from the group consistingof (i) eliciting an immune response against an IL-12 protein having anamino acid sequence selected from the group consisting of SEQ ID NO:39,SEQ ID NO:44, SEQ ID NO:62, and SEQ ID NO:67, (ii) selectively bindingto an antibody raised against an IL-12 protein having an amino acidsequence selected from the group consisting of SEQ ID NO:27, SEQ IDNO:30, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:47, SEQ ID NO:50, SEQ IDNO:53, and SEQ ID NO:59, SEQ ID NO:102, SEQ ID NO:105, SEQ ID NO:108,SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:62, and/or SEQ ID NO:67, and (iii)exhibiting IL-12 activity. The present invention also includesrecombinant molecules, recombinant viruses and recombinant cellscomprising such IL-18, caspase-1, and IL-12 single chain nucleic acidmolecules and methods to produce such nucleic acid molecules,recombinant molecules, recombinant viruses and recombinant cells.

[0012] The present invention also includes an antibody that selectivelybinds to a protein of the present invention as well as methods toproduce and use such proteins or antibodies. By selectively is meant anantibody that binds to a protein of the present invention, but does notbind a similar protein of another species.

[0013] One aspect of the present invention is a therapeutic compositionthat, when administered to an animal, regulates an immune response inthe animal. Such a therapeutic composition includes at least one of thefollowing protective compounds: an IL-18, caspase-1, or IL-12 singlechain protein of the present invention, a mimetope of any of theproteins, a multimeric form of any of the proteins, an isolated nucleicacid molecule of the present invention, an antibody that selectivelybinds any of the proteins, and/or an inhibitor of a protein activityidentified by its ability to inhibit the activity of any of theproteins. Also included is a method to regulate an immune response byadministering such a therapeutic composition to an animal.

[0014] The present invention also includes a method to produce a proteinof the present invention; such a method includes the step of culturing arecombinant cell capable of expressing a protein being encoded by anucleic acid molecule of the present invention.

[0015] Another embodiment of the present invention is a method toidentify a compound capable of regulating an immune response in ananimal, a method selected from the group consisting of: (a) contactingan isolated feline IL-18 protein with a putative inhibitory compoundunder conditions in which, in the absence of the compound, the proteinhas T cell stimulating activity inducing T cells to make interferongamma, and determining if the putative inhibitory compound inhibits thatactivity; (b) contacting an isolated feline caspase-1 protein with aputative inhibitory compound under conditions in which, in the absenceof the compound, the protein cleaves precursor form of IL-18 resultingin biologically active IL-18, and determining if the putative inhibitorycompound inhibits that activity; and (c) contacting an isolated IL-12single chain protein with a putative inhibitory compound underconditions in which, in the absence of the compound, the protein has Tcell proliferation stimulating activity, and determining if the putativeinhibitory compound inhibits that activity.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention provides for isolated feline and canineproteins, nucleic acid molecules encoding such proteins, antibodiesraised against such proteins and/or inhibitors of such proteins ornucleic acid molecules. Specifically, the present invention provides forisolated feline IL-18, feline caspase-1, and feline and canine IL-12single chain proteins and nucleic acid molecules as well as antibodiesraised against such proteins, and/or inhibitors of such proteins ornucleic acid molecules. Also included in the present invention is theuse of these proteins, nucleic acid molecules, antibodies, inhibitorsand/or other compounds derived therefrom as therapeutic compositions toregulate the immune response of an animal as well as in otherapplications, such as those disclosed below.

[0017] One embodiment of the present invention is an isolated proteinthat includes a feline IL-18 protein, a feline caspase-1 protein, afeline IL-12 single chain protein and/or a canine IL-12 single chainprotein. As used herein, a feline and/or canine protein refers to aprotein. As used herein, a protein of the present invention is a proteinthat is isolated from a felid or a canid or is derived therefrom and canbe produced by methods known in the art, such as, for example, usingrecombinant DNA technology or by chemical synthesis. As such, a felineor canine protein of the present invention includes natural forms aswell as any variants thereof, such as a feline or canine protein thathas been altered in a manner known to those skilled in the art, such asthose methods disclosed herein. As used herein, a feline or canineprotein does not refer to a mouse or human protein.

[0018] Similarly, a feline or canine nucleic acid molecule of thepresent invention includes a feline IL-18 nucleic acid molecule, afeline caspase-1 nucleic acid molecule, a feline IL-12 single chainnucleic acid molecule and/or canine IL-12 single chain nucleic acidmolecule. As used herein a feline or canine nucleic acid molecule of thepresent invention refers to a nucleic acid molecule that includes anucleic acid molecule that encodes a protein of the present inventionand/or a complement thereof. As such, a feline IL-18 nucleic acidmolecule, a feline caspase-1 nucleic acid molecule, a feline IL-12single chain nucleic acid molecule or a canine IL-12 single chainnucleic acid molecule of the present invention is a nucleic acidmolecule that encodes a feline IL-18 protein, a feline caspase-1protein, a feline IL-12 single chain protein or a canine IL-12 singlechain protein, respectively, and/or that is a complement thereof. Asused herein, a feline or canine nucleic acid molecule of the presentinvention is a nucleic acid molecule that is isolated from a felid orcanid or is derived therefrom and can be produced using methods known inthe art, such as, for example, recombinant DNA technology, or bychemical synthesis. As such, a feline or canine nucleic acid molecule ofthe present invention includes natural forms as well as any variantsthereof, such as a feline or canine nucleic acid molecule that has beenaltered in a manner known to those skilled in the art, such as thosemethods disclosed herein. As used herein, a feline or canine nucleicacid molecule does not refer to a mouse or human nucleic acid molecule.

[0019] According to the present invention, an isolated, or biologicallypure, nucleic acid molecule or protein, is a nucleic acid molecule orprotein that has been removed from its natural milieu. As such,“isolated” and/or “biologically pure” do not necessarily reflect theextent to which the nucleic acid molecule or protein has been purified.“Proteins” are defined as any compounds which comprise amino acids,including peptides, polypeptides and fusion proteins. It is to be notedthat the term “a” or “an” entity refers to one or more of that entity;for example, a protein refers to one or more proteins or at least oneprotein. As such, the terms “a” (or “an”), “one or more” and “at leastone” can be used interchangeably herein. It is also to be noted that theterms “comprising”, “including”, and “having” can be usedinterchangeably. Furthermore, an item “selected from the groupconsisting of” refers to one or more of the items in that group,including combinations thereof. The term “fragment” refers to any subsetof the referent nucleic acid molecule. Furthermore, the term “linked inframe” refers to nucleic acid fragment joined to another nucleic acidfragment in a manner such that the molecule is able to be expressed whentransformed into a host cell.

[0020] As used herein, a felid refers to any member of the felid family(i.e. the family Felidae), including, but not limited to, domestic cats,and wild cats such as tigers, lions, and lynx. Similarly, the termfeline refers to “of the family Felidae”.

[0021] As used herein, a canid refers to any member of the canid family(i.e. the family Canidae), including, but not limited to, domestic dogs,and wild canids such as wolves, foxes, and coyotes. Similarly, the termcanine refers to “of the family Canidae”.

[0022] Nucleic acid molecules of the present invention of known lengthisolated from Felis catus are denoted as follows: a feline IL-18 nucleicacid molecule is denoted as nFeIL-18_(x), wherein “x” refers to thenumber of nucleotides in that molecule; for example, nFeIL-18₆₀₇ refersto a feline IL-18 nucleic acid molecule of 607 nucleotides in length;and in a similar fashion, a feline Casp-1 nucleic acid molecule oflength “x” is referred to as nFeCasp-1_(x), a feline IL-12 single chainnucleic acid molecule of length “x” is referred to as nFeIL-12_(x), afeline IL-12p35 subunit nucleic acid molecule of length “x” is referredto as nFeIL-12p35_(x) and a feline IL-12p40 subunit nucleic acidmolecule of length “x” is referred to as nFeIL-12p40_(x). Similarly,Felis catus IL-18, Casp-1, IL-12 single chain, IL-12p35 subunit, andIL-12p40 subunit proteins of the present invention of known length aredenoted PFeIL-18_(x), PFeCasp-1_(x), PFeIL-12_(x), PFeIL-12p35_(x), andPFeIL-12p40_(x) respectively.

[0023] Nucleic acid molecules of the present invention of known lengthisolated from Canis familiaris are denoted as follows: a canine IL-12single chain is denoted as nCaIL-12_(x), wherein “x” refers to thenumber of nucleotides in that molecule; for example, nCaIL-12₁₆₀₂ refersto a canine IL-12 single chain nucleic acid molecule of 1602 nucleotidesin length and in a similar fashion, a canine IL-12 single chain nucleicacid molecule of length “x” is referred to as nCaIL-12p35_(x) and acanine IL-12p40 subunit nucleic acid molecule of length “x” is referredto as nCaIL-12p40_(x). Similarly, Canis familiaris IL-12 single chainproteins of the present invention of known length isolated from aredenoted PCaIL-12_(x), PCaIL-12p35_(x), or PCaIL-12p40_(x) respectively.The present invention includes nucleic acid molecules selected from thegroup consisting of nCaIL-12p35₅₉₁, nCaIL-12p40₂₂₆₇, nCaIL-12p40₁₀₀₂,nCaIL-12p40₉₈₇, nCaIL-12₁₅₉₉, and nCaIL-12₁₅₃₃.

[0024] The present invention includes nucleic acid molecules thatinclude one or more of the following nucleic acid sequences: SEQ IDNO:1, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:14,SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29,SEQ ID NO:32, SEQ ID NO:35, SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:43,SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:58, SEQ ID NO:61,SEQ ID NO:64 and/or SEQ ID NO:66, and/or a complements of these nucleicacid sequences, i.e. SEQ ID NO:3, SEQ ID NO:6, SEQ ID NO:10, SEQ IDNO:13, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:22, SEQ ID NO:25, SEQ IDNO:28, SEQ ID NO:31, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:40, SEQ IDNO:45, SEQ ID NO:48, SEQ ID NO:51, SEQ ID NO:54, SEQ ID NO:60, SEQ IDNO:63, and/or SEQ ID NO:68, respectively. Complements are defined as twosingle strands of nucleic acid in which the nucleotide sequences aresuch that the strands will hybridize as a result of base pairingthroughout their full length; i.e., these sequences are fullycomplementary. Such nucleic acid sequences are further described hereinand can be easily be determined by those skilled in the art. It shouldbe noted that since nucleic acid sequencing technology is not entirelyerror-free, nucleic acid and protein sequences presented hereinrepresent apparent nucleic acid and amino acid sequences of the isolatednucleic acid molecules and proteins, respectively, of the presentinvention.

[0025] As used herein, an isolated feline IL-18, feline caspase-1,feline IL-12p40 subunit, feline IL-12p35 subunit, feline IL-12 singlechain, canine IL-12p40 subunit, canine IL-12p35, and/or canine IL-12single chain protein of the present invention can be a full-lengthprotein or any homolog of such a protein, including truncated forms ofthe protein. An isolated IL-18 protein of the present invention,including a homolog, can be identified in a straight-forward manner bythe protein's ability to elicit an immune response against, (or to) anIL-18 protein, whether the protein has IL-18 activity, such as T cellstimulating activity, or selectively binding to an antibody raisedagainst an IL-18 protein. An isolated caspase-1 protein of the presentinvention may be identified in a straight-forward manner by theprotein's ability to elicit an immune response against, (or to) acaspase-1 protein, whether the protein has caspase-1 activity, such ascleaving the precursor form of IL-18 resulting in a biologically activeIL-18, or selectively binding to an antibody raised against a caspase-1protein. A IL-12 single chain protein of the present invention may beidentified in a straight-forward manner by the protein's ability toelicit an immune response against, (or to) an IL-12 protein, includingthe p35 or p40 subunits, whether the protein has IL-12 activity, such asT cell stimulating activity, or selectively binding to an antibodyraised against an IL-12 protein, including the p35 or p40 subunits.Examples of protein homologs of the present invention includes proteinsof the present invention in which amino acids have been deleted (e.g. atruncated version of the protein, such as a peptide), inserted,inverted, substituted and/or derivatized (e.g. by glycosylation,phosphorylation, acetylation, myristoylation, prenylation,palmitoylation, amidation and/or addition of glycerophosphatidylinositol) such that the protein homolog include at least one epitopecapable of eliciting an immune response against the parent protein,where the term parent refers to the longer and/or full-length proteinthat the homolog is derived from. The ability of a protein to effect animmune response can be measured using techniques known to those skilledin the art. As used herein, the term “epitope” refers to the smallestportion of a protein capable of selectively binding to the antigenbinding site of an antibody. It is well accepted by those skilled in theart that the minimal size of a protein epitope capable of selectivelybinding to the antigen binding site of an antibody is about five or sixto seven amino acids.

[0026] Proteins of the present invention include variants of afull-length protein of the present invention. Such variants includeproteins that are less than full-length. As used herein, variants of thepresent invention refer to nucleic acid molecules that arenaturally-occurring a defined below, and may result from alternative RNAsplicing, alternative termination of an amino acid sequence or DNArecombination. Examples of variants include allelic variants as definedbelow. It is to be noted that a variant is an example of a homolog ofthe present invention.

[0027] Proteins of the present invention are encoded by nucleic acidmolecules of the present invention. As used herein, an IL-18 nucleicacid molecule includes sequences related to a natural feline IL-18 gene.As used herein, a caspase-1 protein includes nucleic acid sequencesrelated to a natural feline caspase-1 gene. As used herein, an IL-12single chain nucleic acid molecule includes sequences related to anatural canine or feline IL-12 gene, IL-12p35 gene, and/or IL-12p40gene. As used herein, a feline IL-18, a feline caspase-1, and or afeline or canine IL-12 single chain refers to the natural genomicelements that encode a feline IL-18, a feline caspase-1, and or a felineor canine IL-12 single chain, and includes all regions such asregulatory regions that control production of the protein encoded by thegene) such as, but not limited to, transcription, translation orpost-translation control regions) as well as the coding region itself,and any introns or non-translated coding regions. As used herein, a genethat “includes” or “comprises” a sequence may include that sequence inone continuous array, or may include the sequence of fragmented exons.As used herein, the term “coding region” refers to a continuous lineararray of nucleotides that translates into a protein. A full-lengthcoding region is that region that is translated into a full-length,i.e., a complete protein as would be initially translated in its naturalmilieu, prior to any post-translational modifications.

[0028] In one embodiment of the present invention, isolated proteins areencoded by nucleic acid molecules that hybridize under stringenthybridization conditions to the non-coding strand of nucleic acidmolecules encoding proteins. The minimal size of a protein of thepresent invention (4-6 amino acids) is a size sufficient to be encodedby a nucleic acid molecule capable of forming a stable hybrid, i.e.,hybridizing under stringent hybridization conditions, with thecomplementary sequence of a nucleic acid molecule encoding thecorresponding natural protein. The size of a nucleic acid moleculeencoding such a protein is dependent on the nucleic acid composition andthe percent homology between the nucleic acid molecule and thecomplementary nucleic acid sequence. It can easily be understood thatthe extent of homology required to form a stable hybrid under stringentconditions can vary depending on whether the homologous sequences areinterspersed throughout a given nucleic acid molecule or are clustered,i.e. localized, in distinct regions on a given nucleic acid molecule.

[0029] The minimal size of a feline IL-18, feline caspase-1, and/orcanine or feline IL-12 single chain protein homolog/portion/fragment ofthe present invention is a size sufficient to be encoded by a nucleicacid molecule capable of forming a stable hybrid (i.e. hybridize understringent hybridization conditions) with the complementary sequence of anucleic acid molecule encoding the corresponding natural protein.Stringent hybridization conditions are determined based on definedphysical properties of the gene to which the nucleic acid molecule isbeing hybridized, and can be defined mathematically. Stringenthybridization conditions are those experimental parameters that allow anindividual skilled in the art to identify significant similaritiesbetween heterologous nucleic acid molecules. These conditions are wellknown to those skilled in the art. See, for example, Sambrook, et al.,1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor LabsPress, and Meinkoth, et al., 1984, Anal. Biochem. 138, 267-284, each ofwhich is incorporated herein by this reference. As explained in detailin the cited references, the determination of hybridization conditionsinvolves the manipulation of a set of variables including the ionicstrength (M, in moles/liter), the hybridization temperature (°C.), theconcentration of nucleic acid helix destabilizing agents, such asformamide, the average length of the shortest hybrid duplex (n), and thepercent G+C composition of the fragment to which an unknown nucleic acidmolecule is being hybridized. For nucleic acid molecules of at leastabout 150 nucleotides, these variables are inserted into a standardmathematical formula to calculate the melting temperature, or T_(m), ofa given nucleic acid molecule. As defined in the formula below, T_(m) isthe temperature at which two complementary nucleic acid molecule strandswill disassociate, assuming 100% complementarity between the twostrands:

T _(m)=81.5° C.+16.6 log M+0.41(% G+C)−500/n−0.61(% formamide).

[0030] For nucleic acid molecules smaller than about 50 nucleotides,hybrid stability is defined by the dissociation temperature (T_(d)),which is defined as the temperature at which 50% of the duplexesdissociate. For these smaller molecules, the stability at a standardionic strength is defined by the following equation:

T _(d)=4(G+C)+2(A+T).

[0031] A temperature of 5° C. below T_(d) is used to detecthybridization between perfectly matched molecules.

[0032] Also well known to those skilled in the art is how base pairmismatch, i.e. differences between two nucleic acid molecules beingcompared, including non-complementarity of bases at a given location,and gaps due to insertion or deletion of one or more bases at a givenlocation on either of the nucleic acid molecules being compared, willaffect T_(m) or T_(d) for nucleic acid molecules of different sizes. Forexample, T_(m) decreases about 1° C. for each 1% of mismatched basepairs for hybrids greater than about 150 bp, and T_(d) decreases about5° C. for each mismatched base pair for hybrids below about 50 bp.Conditions for hybrids between about 50 and about 150 base pairs can bedetermined empirically and without undue experimentation using standardlaboratory procedures well known to those skilled in the art. Thesesimple procedures allow one skilled in the art to set the hybridizationconditions, by altering, for example, the salt concentration, theformamide concentration or the temperature, so that only nucleic acidhybrids with greater than a specified % base pair mismatch willhybridize. Stringent hybridization conditions are commonly understood bythose skilled in the art to be those experimental conditions that willallow about 30% or less base pair mismatch, i.e., at least about 85%identity. Because one skilled in the art can easily determine whether agiven nucleic acid molecule to be tested is less than or greater thanabout 50 nucleotides, and can therefore choose the appropriate formulafor determining hybridization conditions, he or she can determinewhether the nucleic acid molecule will hybridize with a given gene orspecified nucleic acid molecule under stringent hybridization conditionsand similarly whether the nucleic acid molecule will hybridize underconditions designed to allow a desired amount of base pair mismatch.

[0033] Hybridization reactions are often carried out by attaching thenucleic acid molecule to be hybridized to a solid support such as amembrane, and then hybridizing with a labeled nucleic acid molecule,typically referred to as a probe, suspended in a hybridization solution.Examples of common hybridization reaction techniques include, but arenot limited to, the well-known Southern and northern blottingprocedures. Typically, the actual hybridization reaction is done undernon-stringent conditions, i.e., at a lower temperature and/or a highersalt concentration, and then high stringency is achieved by washing themembrane in a solution with a higher temperature and/or lower saltconcentration in order to achieve the desired stringency.

[0034] In one embodiment, an IL-18 gene of the present inventionincludes the nucleic acid molecule SEQ ID NO:1, as well as thecomplement of SEQ ID NO:1. Nucleic acid sequence SEQ ID NO:1 representsthe deduced sequence of the coding strand of a cDNA (complementary DNA)denoted herein as nucleic acid molecule nFeIL-18-N₅₁₄, the production ofwhich is disclosed in the Examples. SEQ ID NO:1 comprises an apparentpartial coding region of nFeIL-18, coding for the N-terminal portion offeline IL-18 protein. The complement of SEQ ID NO:1 (represented hereinby SEQ ID NO:3) refers to the nucleic acid sequence of the strand fullycomplementary to the strand having SEQ ID NO:1, which can easily bedetermined by those skilled in the art. Likewise, a nucleic acidsequence complement of any nucleic acid sequence of the presentinvention refers to the nucleic acid sequence complement of any nucleicacid sequence of the present invention tat is fully complementary (i.e.can form a double helix with) the strand for which the sequence iscited. It should be noted that since nucleic acid sequencing technologyis not entirely error-free, SEQ ID NO:1 (as well as other nucleic acidand protein sequences presented herein) represents an apparent nucleicacid sequence of the nucleic acid molecule encoding an immunoregulatoryprotein of the present invention.

[0035] Another IL-18 gene of the present invention includes the nucleicacid molecule SEQ ID NO:4, as well as the complement represented by SEQID NO:6. Nucleic acid sequence SEQ ID NO:4 represents the deducedsequence of the coding strand of a cDNA denoted herein as nucleic acidmolecule nFeIL-18-C₅₀₂, the production of which is disclosed in theexamples. Nucleic acid nFeIL-18-C₅₀₂ represents an apparent partialcoding region of FeIL-18, encoding a partial C-terminal region of thefeline IL-18 protein. Another IL-18 gene of the present inventionincludes the nucleic acid molecule SEQ ID NO:7, as well as thecomplement represented by SEQ ID NO:10. Nucleic acid sequence SEQ IDNO:7 represents the deduced sequence of the coding strand of a cDNAdenoted herein as nucleic acid molecule nFeIL-18₆₀₇, the production ofwhich is disclosed in the examples. Nucleic acid nFeIL-18₆₀₇ representsan apparent full-length coding region of the feline IL-18 protein.Another IL-18 gene of the present invention includes the nucleic acidmolecule SEQ ID NO:9, as well as the complement represented by SEQ IDNO:41. Nucleic acid sequence SEQ ID NO:9 represents the deduced sequenceof the coding strand of a cDNA denoted herein as nucleic acid moleculenFe IL-18₅₇₆, the production of which is disclosed in the examples.Nucleic acid molecule nFe IL-18₅₇₆ represents the coding region for anapparent precursor protein to a mature feline IL-18 protein. AnotherIL-18 gene of the present invention includes the nucleic acid moleculeSEQ ID NO:11, as well as the complement represented by SEQ ID NO:13.Nucleic acid sequence SEQ ID NO:11 represents the deduced sequence ofthe coding strand of a cDNA denoted herein as nucleic acid molecule nFeIL-18₄₇₁, the production of which is disclosed in the Examples. Nucleicacid molecule nFe IL-18₄₇₁, represents the coding region for an apparentmature IL-18 protein. The putative cleavage site for the mature IL-18protein is between amino acid positions 35 and 36 of SEQ ID NO:8,representing PFeIL-18₁₉₂, which is the predicted amino acid sequence ofthe full-length IL-18 protein (i.e., containing signal, or leader,peptide). SEQ ID NO:12 represents the predicted amino acid sequence ofthe mature IL-18 protein (i.e., without the signal, or leader,sequence), also denoted as PFeIL-18₁₅₇.

[0036] In another embodiment, a caspase-1 gene of the present inventionincludes the nucleic acid sequence SEQ ID NO:14, as well as thecomplement represented by SEQ ID NO:16. Nucleic acid sequence SEQ IDNO:14 represents the deduced sequence of the coding strand of a cDNAdenoted herein as nucleic acid molecule nFeCasp-1₁₂₃₃, the production ofwhich is disclosed in the Examples. Nucleic acid molecule nFeCasp-1₁₂₃₃represents the coding region for an apparent full-length felinecaspase-1 protein and includes a human primer sequence. Anothercaspase-1 protein of the present invention includes the nucleic acidsequence SEQ ID NO:17, as well as the complement represented by SEQ IDNO:19. Nucleic acid sequence SEQ ID NO:17 represents the deducedsequence of the coding strand of a cDNA denoted herein as nucleic acidmolecule nFeCasp-1-N₅₂₆, the production of which is disclosed in theExamples. Nucleic acid molecule nFeCasp-1-N₅₂₆ represents the codingregion for the apparent N-terminal region of the feline caspase-1protein. Another caspase-1 protein of the present invention includes thenucleic acid molecule SEQ ID NO:20, as well as the complementrepresented by SEQ ID NO:22. Nucleic acid sequence SEQ ID NO:20represents the deduced sequence of a coding strand of a cDNA denotedherein as nucleic acid molecule nFeCasp-1-C₅₀₀, the production of whichis disclosed in the Examples. Nucleic acid molecule nFeCasp-1-C₅₀₀represents the coding region for the apparent C-terminal region of thefeline caspase-1 protein. Another caspase-1 protein of the presentinvention includes the nucleic acid molecule SEQ ID NO:23, as well asthe complement represented by SEQ ID NO:25. Nucleic acid sequence SEQ IDNO:23 represents the deduced sequence of a coding strand of a cDNAdenoted herein as nucleic acid molecule nFeCasp-1₁₂₃₀, the production ofwhich is disclosed in the examples. Nucleic acid molecule nFeCasp-1₁₂₃₀represents the coding region for the apparent full-length felinecaspase-1 protein, denoted herein as PFeCasp-1₄₁₀, represented herein asSEQ ID NO:24.

[0037] In another embodiment, feline IL-12 single chain proteins of thepresent invention contain both a mature IL-12 p35 subunit and afull-length IL-12 p40 subunit, joined by a linker. An IL-12 single chaingene of the present invention includes the nucleic acid sequence SEQ IDNO:38, as well as the complement represented by SEQ ID NO:40. Nucleicacid sequence SEQ ID NO:38 represents the deduced sequence of the codingstrand of a cDNA denoted herein as nucleic acid molecule nFeIL-12₁₅₉₉,the production of which is disclosed in the Examples. Nucleic acidmolecule nFeIL-12₁₅₉₉ represents the coding region encoding a singlechain full-length feline IL-12 protein, which includes the coding regionfor a full-length (i.e. containing signal, or leader, sequence) IL-12p40 subunit, a linker of the present invention, and the coding regionfor a mature (i.e. not containing signal, or leader, sequence) IL-12 p35subunit. SEQ ID NO:38 comprises a sequence that includes both thenucleic acid sequence SEQ ID NO:29 (nucleic acid sequence SEQ ID NO:29represents the deduced sequence of the coding strand of a cDNA denotedherein as nucleic acid molecule nFeIL-12p40₉₈₇, which represents thecoding region encoding the full-length feline IL-12 p40 subunit, whereasSEQ ID NO:31 represents the complement of SEQ ID NO:29) and SEQ ID NO:35(nucleic acid sequence SEQ ID NO:35 represents the deduced sequence ofthe coding strand of a cDNA denoted herein as nucleic acid moleculenFeIL-12p35₅₉₁, which represents the coding region encoding the maturefeline IL-12 p35 subunit, whereas SEQ ID NO:37 represents the complementof SEQ ID NO:35). Translation of SEQ ID NO:38 yields a predicted proteindenoted herein as PFeIL-12₅₃₃, also denoted as SEQ ID NO:39.

[0038] In another embodiment, feline IL-12 single chain proteins of thepresent invention contain both a mature IL-12 p35 subunit and an matureIL-12 p40 subunit, joined by a linker. An IL-12 single chain gene of thepresent invention includes the nucleic acid sequence SEQ ID NO:43, aswell as the complement represented by SEQ ID NO:45. Nucleic acidsequence SEQ ID NO:43 represents the deduced sequence of the codingstrand of a cDNA denoted herein as nucleic acid molecule nFeIL-12₁₅₃₃,the production of which is disclosed in the Examples. Nucleic acidmolecule nFeIL-12₁₅₃₃ represents the coding region encoding a singlechain mature feline IL-12 protein. SEQ ID NO:33 comprises a sequencethat includes both the nucleic acid sequence SEQ ID NO:26 (nucleic acidsequence SEQ ID NO:26 represents the deduced sequence of the codingstrand of a cDNA denoted herein as nucleic acid molecule nFeIL-12p40₉₈₅,which represents the coding region encoding the mature feline IL-12 p40subunit, whereas SEQ ID NO:28 represents the complement of SEQ ID NO:26)and SEQ ID NO:35 (nucleic acid sequence SEQ ID NO:35 represents thededuced sequence of the coding strand of a cDNA denoted herein asnucleic acid molecule nFeIL-12p35₅₉₁, which represents the coding regionencoding the mature feline IL-12 p35 subunit, whereas SEQ ID NO:37represents the complement of SEQ ID NO:35). Translation of SEQ ID NO:43yields a predicted protein denoted herein as PFeIL-12₅₁₁, also denotedas SEQ ID NO:44.

[0039] In another embodiment, canine IL-12 single chain proteins andnucleic acid molecules of the present invention contain both a matureIL-12 p35 subunit and a full-length IL-12 p40 subunit, joined by alinker. An IL-12 single chain gene of the present invention includes thenucleic acid sequence SEQ ID NO:61, as well as the complementrepresented by SEQ ID NO:63. Nucleic acid sequence SEQ ID NO:61represents the deduced sequence of the coding strand of a cDNA denotedherein as nucleic acid molecule nCaIL-12₁₅₉₉, the production of which isdisclosed in the Examples. Nucleic acid molecule nCaIL-12₁₅₉₉ representsthe coding region encoding a single chain full-length canine IL-12protein, which includes the coding region for a full-length (i.e.containing signal, or leader, sequence), IL-14 p40 subunit, a linker ofthe present invention, and the coding region for a mature, (i.e., notcontaining signal, or leader, sequence) IL-12 p35 subunit. SEQ ID NO:61comprises a nucleic acid sequence that includes both the nucleic acidsequence SEQ ID NO:58 (nucleic acid SEQ ID NO:58 represents the deducedsequence of the coding strand of a cDNA denoted herein as nucleic acidmolecule nCaIL-12 ₉₈₇, which represents the coding region encoding thefull-length canine IL-12 p40 subunit, whereas SEQ ID NO:60 representsthe complement of SEQ ID NO:58) and SEQ ID NO:49 (nucleic acid sequenceSEQ ID NO:49 represents the deduced sequence of the coding strand of acDNA denoted herein as nucleic acid molecule nFeIL-12p35₅₉₁, whichrepresents the coding region encoding the mature canine IL-12 subunit,whereas SEQ ID NO:51 represents the complement of SEQ ID NO:49.Translation of SEQ ID NO:61 yields a predicted protein denoted herein asPCaIL-12₅₃₃, also denoted as SEQ ID NO:62.

[0040] In another embodiment, canine IL-12 single chain proteins andnucleic acid molecules of the present invention contain both a matureIL-12 p35 subunit and a mature IL-12 p40 subunit, joined by a linker. AnIL-12 single chain gene of the present invention includes the nucleicacid sequence SEQ ID NO:66, as well as the complement represented by SEQID NO:68. Nucleic acid sequence SEQ ID NO:66 represents the deducedsequence of the coding strand of a cDNA denoted herein as nucleic acidmolecule nCaIL-12₁₅₃₃, the production of which is disclosed in theExamples. Nucleic acid molecule nCaIL-12₁₅₃₃ represents the codingregion encoding a single chain full-length canine IL-12 protein, whichincludes the coding region for a full-length (i.e. containing signal, orleader, sequence), IL-14 p40 subunit, a linker of the present invention,and the coding region for a mature, (i.e., not containing signal, orleader, sequence) IL-12 p35 subunit. SEQ ID NO:66 comprises a nucleicacid sequence that includes both the nucleic acid sequence SEQ ID NO:52(nucleic acid SEQ ID NO:52 represents the deduced sequence of the codingstrand of a cDNA denoted herein as nucleic acid molecule nCaIL-12, whichrepresents the coding region encoding the mature canine IL-12 p40subunit, whereas SEQ ID NO:54 represents the complement of SEQ ID NO:52)and SEQ ID NO:49 (nucleic acid sequence SEQ ID NO:49 represents thededuced sequence of the coding strand of a cDNA denoted herein asnucleic acid molecule nFeIL-12p35₅₉₁, which represents the coding regionencoding the mature canine IL-12 subunit, whereas SEQ ID NO:51represents the complement of SEQ ID NO:49. Translation of SEQ ID NO:66yields a predicted protein denoted herein as PCaIL-12₅₁₁, also denotedas SEQ IID NO:67.

[0041] Nucleic acid molecules and proteins of the present inventionhaving specific sequence identifiers are described in Table 1. TABLE 1Sequence identification numbers (SEQ ID NOs) and their correspondingnucleic acid molecule or proteins. SEQ ID NO description 1 nFeIL-18-N₅₁₄coding strand 2 PFeIL-18-N₁₃₃ 3 nFeIL-18-N₅₁₄ complementary strand 4nFeIL-18-C₅₀₂ coding strand 5 PFeIL-18-C₁₅₄ 6 nFeIL-18-C₅₀₂complementary strand 7 nFeIL-18₆₀₇ coding strand 8 PFeIL-18₁₉₂ 9nFeIL-18₅₇₆ coding strand: coding sequence for full-length feline IL-18protein 10 nFeIL-18₆₀₇ complementary strand to SEQ ID NO: 7 11nFeIL-18₄₇₁ coding strand: coding sequence for mature feline IL-18protein 12 PFeIL-18₁₅₇ 13 nFeIL-18₄₇₁ complementary strand 14nFeCasp-1₁₂₃₃ coding strand 15 PFeCasp-1₄₁₀ 16 nFeCasp-1₁₂₃₃complementary strand 17 nFeCasp-1-N₅₂₆ coding strand 18 PFeCasp-1-N₁₆₉19 nFeCasp-1-N₅₂₆ complementary strand 20 nFeCasp-1-C₅₀₀ coding strand21 PFeCasp-1-C₁₂₀ 22 nPeCasp-1-C₅₀₀ complementary strand 23nFeCasp-1₁₂₃₀ coding strand: coding sequence for feline caspase-1protein 24 PFeCasp-1₄₁₀ 25 nFeCasp-1₁₂₃₀ complementary strand 26nFeIL-12p40₉₂₁ coding strand: coding sequence for feline mature IL-12p40subunit 27 PFeIL-12p40₃₀₇ 28 nFeIL-12p40₉₂₁ complementary strand 29nFeIL-12p40₉₈₇ coding strand: coding sequence for feline full-lengthIL-12p40 subunit 30 PFeIL-12p40₃₂₉ 31 nFeIL-12p40₉₈₇ complementarystrand 32 nFeIL-12p35₆₆₆ coding strand: coding sequence for felinefull-length IL-12p35 subunit 33 PFeIL-12p35₂₂₂ 34 nFeIL-12p35₆₆₆complementary strand 35 nFeIL-12p35₅₉₁ coding strand: coding sequencefor feline mature IL-12p35 subunit 36 PFeIL-12p35-N₁₈₇ 37 nFeIL-12p35₅₉₁complementary strand 38 nFeIL-12₁₅₉₉ coding strand 39 PFeIL-12₅₃₃ 40nFeIL-12₁₅₉₉ complementary strand 41 nFeIL-18₅₇₆ complementary strand toSEQ ID NO: 9 42 not used--inactive 43 nFeIL-12₁₅₃₃ coding strand 44PFeIL-12₅₁₁ 45 nFeIL-12₁₅₃₃ complementary strand 46 nCaIL-12p35₆₆₆coding strand: coding strand for canine full-length IL-12p35 subunit 47PCaIL-12p35₂₂₂ 48 nCaIL-12p35₆₆₆ complementary strand 49 nCaIL-12p35₅₉₁coding strand 50 PCaIL-12p35₁₉₇ 51 nCaIL-12p35₅₉₁ complementary strand52 nCaIL-12p40₉₂₁ coding strand: coding sequence for mature form canineIL-12 p40 subunit 53 PCaIL-12p40₃₀₇ 54 nCaIL-12p40₉₂₁ reverse complement55 nFeIL-12p40-N₉₈₅ coding sequence 56 PCaIL-12p40-N₃₂₈ 57nFeIL-12p40-N₉₈₅ complementary strand 58 nCaIL-12p40₉₈₇ coding strand:coding sequence for full-length canine IL-12 p40 subunit 59PCaIL-12p40₃₂₉ 60 nCaIL-12p40₉₈₇ complementary strand 61 nCaIL-12₁₅₉₉coding strand 62 PCaIL-12₅₃₃ 63 nCaIL-12₁₅₉₉ complementary strand 64 notused--inactive 65 not used--inactive 66 nCaIL-12₁₅₃₃ coding strand 67PCaIL-12₅₁₁ 68 nCaIL-12₁₅₃₃ complementary strand 101 nFeIL-12p35-N₅₆₁coding strand 102 PFeIL-12p35-N₁₈₇ 103 nFeIL-12p35-N₅₆₁ complementarystrand 104 nCaIL-12p35₁₄₅₅ coding strand 105 PCaIL-12p35₂₂₂ 106nCaIL-12p35₁₄₅₅ complementary strand 107 nCaIL-12p40₂₂₆₇ coding strand108 PcaIL-12p40₃₂₉ 109 nCaIL-12p40₂₂₆₇ complementary strand

[0042] Particularly preferred nucleic acid molecules encoding felineIL-18 proteins are nFeIL-18-N₅₁₄, nFeIL-18-C₅₀₂, nFeIL-18₆₀₇,nFeIL-18₅₇₆, and nFeIL-18₄₇₁, the coding strands of which arerepresented by SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:9 andSEQ ID NO:11, respectively.

[0043] Particularly preferred nucleic acid molecules encoding felinecaspase-1 proteins are nFeCasp-1₁₂₃₃, nFeCasp-1-N₅₂₆, nFeCasp-1-C₅₀₀ andnFeCasp-1₁₂₃₀, the coding strands of which are represented by SEQ IDNO:14, SEQ ID NO:17, SEQ ID NO:20, and SEQ ID NO:23 respectively.

[0044] Particularly preferred nucleic acid molecules encoding canine andfeline IL-12 p35 and p40 subunit proteins are nFeIL-12p40-N₉₈₅,nFeIL-12p40₉₈₇, FeIL-12p40₉₂₁, nFeIL-12p35₆₆₆, nFeIL-12p35-N₅₆₁,nFeIL-12p35₅₉₁, nCaIL-12p35₆₆₆, nCaIL-12p35₁₄₅₅, nCaIL-12p35₅₉₁,nCaIL-12p40₂₂₆₇, nCaIL-12p40₉₂₁, and nCaIL-12p40₉₈₇. Coding strands ofwhich are represented by SEQ ID NO:28, SEQ ID NO:31, SEQ ID NO:32, SEQID NO:35, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:55, SEQ IDNO:58, SEQ ID NO:101, SEQ ID NO:104, and SEQ ID NO:107.

[0045] Additional preferred nucleic acid molecules encoding canine andfeline IL-12 single chain proteins are nFeIL-12₁₅₃₃, nFeIL-12₁₅₉₉,nCaIL-12₁₅₃₃, nCaIL-12 ₁₅₉₉, the coding strands of which are representedby SEQ ID NO:43, SEQ ID NO:38, SEQ ID NO:61, and SEQ ID NO:66.

[0046] One embodiment of the present invention includes an isolatednucleic acid molecule that is selected from a group of nucleic acidmolecules. One member of this group includes an isolated nucleic acidmolecule that is selected from the group consisting of SEQ ID NO:1, SEQID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:10, SEQ IDNO:9, SEQ ID NO:41, SEQ ID NO:11, and SEQ ID NO:13; and a nucleic acidmolecule comprising at least 70 contiguous nucleotides identical insequence to at least 70 contiguous nucleotides of a nucleic acidsequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3,SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:9, SEQ IDNO:41, SEQ ID NO:11, and SEQ ID NO:13. Another member of this group ofnucleic acid molecules includes an isolated nucleic acid molecule thatis selected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQID NO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23, andSEQ ID NO:25; and a nucleic acid molecule comprising at least 70contiguous nucleotides identical in sequence to at least 70 contiguousnucleotides of a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19,SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:25. Anothermember of this group of nucleic acid molecules includes an isolatednucleic acid molecule that is selected from the group consisting of anucleic acid molecule comprising (a) an isolated nucleic acid moleculecomprising a nucleic acid sequence selected from the group consisting ofSEQ ID NO:26, SEQ ID NO:29, and a nucleic acid sequence comprising atleast 44 contiguous nucleotides identical in sequence to at least 44contiguous nucleotides of a nucleic acid sequence selected from thegroup consisting of SEQ ID NO:26 and SEQ ID NO:9; (b) a nucleic acidlinker of (XXX)_(n), wherein n=0 to 60; and (c) an isolated nucleic acidmolecule comprising a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:32, SEQ ID NO:35, and a nucleic acid moleculecomprising at least 44 contiguous nucleotides identical in sequence toat least 44 contiguous nucleotides of a nucleic acid sequence selectedfrom the group consisting of SEQ ID NO:32 and SEQ ID NO:35, such that anucleic acid molecule of this particular group encodes a feline IL-12protein. Another member of this group of nucleic acid molecules includesan isolate nucleic acid molecule selected from the group consisting of anucleic acid molecule comprising (a) an isolated nucleic acid moleculecomprising a nucleic acid sequence selected from the group consisting ofSEQ ID NO:52 and SEQ ID NO:58, and a nucleic acid sequence comprising atleast 47 contiguous nucleotides identical in sequence to at least 47contiguous nucleotides of a nucleic acid sequence selected from thegroup consisting of SEQ ID NO:46 and SEQ ID NO:49; (b) a nucleic acidlinker of (XXX)_(n) wherein n=0 to 60; and (c) an isolated nucleic acidmolecule comprising a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:46, SEQ ID NO:49, and a nucleic acid moleculecomprising at least 47 contiguous nucleotides identical in sequence toat least 47 contiguous nucleotides of a nucleic acid sequence selectedfrom the group consisting of SEQ ID NO:46 and SEQ ID NO:49, such that anucleic acid molecule of this particular group encodes a canine IL-12single chain protein.

[0047] The phrase, a nucleic acid molecule comprising at least “x”contiguous nucleotides identical in sequence to at least “x” contiguousnucleotides of a nucleic acid molecule selected from the groupconsisting of SEQ ID NO:“y”, refers to an “x”-nucleotide in lengthnucleic acid molecule that is identical in sequence to an “x”-nucleotideportion of SEQ ID NO:“y”, as well as to nucleic acid molecules that arelonger in length than “x”. The additional length may be in the form ofnucleotides that extend from either the 5′ or the 3′ end(s) of thecontiguous identical “x”-nucleotide portion. The 5′ and/or 3′ extensionscan include one or more extensions that have no identity to animmunoregulatory molecule of the present invention, as well asextensions that show similarity or identity to cited nucleic acidssequences or portions thereof.

[0048] Preferred portions, or lengths, for feline IL-18, felinecaspase-1, feline IL-12 single chain, and canine IL-12 single chainnucleic acid molecules of the present invention include nucleic acidmolecules of at least 40 nucleotides in length, at least 43 nucleotidesin length, at least 44 nucleotides in length, at least 47 nucleotides inlength, at least 50 nucleotides in length, at least 55 nucleotides inlength, at least 60 nucleotides in length, at least 65 nucleotides inlength, at least 70 nucleotides in length, at least 75 nucleotides inlength, at least 80 nucleotides in length, at least 85 nucleotides inlength, at least 90 nucleotides in length, at least 95 nucleotides inlength, at least 100 nucleotides in length, at least 120 nucleotides inlength, at least 140 nucleotides in length, at least 160 nucleotides inlength, at least 180 nucleotides in length, at least 200 nucleotides inlength, at least 250 nucleotides in length, at least 300 nucleotides inlength, at least 350 nucleotides in length, at least 400 nucleotides inlength, at least 450 nucleotides in length, at least 500 nucleotides inlength, at least 600 nucleotides in length, at least 700 nucleotides inlength, at least 800 nucleotides in length, at least 900 nucleotides inlength, and a full-length molecule. Particularly preferred portions, orlengths, of the nucleic acid molecules of the present invention includenucleic acids of at least 43 nucleotides, 44 nucleotides, 47nucleotides, 70 nucleotides, and a full length molecule.

[0049] One embodiment of a protein and/or nucleic acid molecule of thepresent invention is a fusion nucleic acid and/or protein that includeseither a feline IL-18, caspase-1, feline IL-12 single chain, and canineIL-12 single chain nucleic acid molecule and/or protein of the presentinvention domain, each attached to one or more fusion segments. Suitablefusion segments for use with the present invention include, but are notlimited to, segments that can: link two or more nucleic acids and/orproteins of the present invention, to form multimeric forms of a nucleicacids and/or protein of the present invention; enhance a nucleic acidmolecules or protein's stability; enhance the biological activity of anucleic acid molecule and/or protein of the present invention; and/orassist in purification a molecule of the present invention (e.g., byaffinity chromatography). A suitable fusion segment can be a domain ofany size that has the desired function (e.g., imparts increasedstability, enhanced activity, and/or simplifies purification of aprotein). Fusion segments can be joined to amino and/or carboxyl terminiof the IL-18-containing domain, or the caspase-1 ligand-containingdomain, or the IL-12 p40-containing domain, or the IL-12 p35-containingdomain, or the IL-12 single chain-containing domain, of a protein and/ornucleic acid and can be susceptible to cleavage in order to enablestraight-forward recovery of the protein and/or nucleic acid molecule.Fusion proteins are preferably produced by culturing a recombinant celltransformed with a fusion nucleic acid molecule that encodes a proteinincluding the fusion segment attached to either the carboxyl and/oramino terminal end of a feline IL-18, feline caspase-1, feline IL-12 p35subunit, feline IL-12 p40 subunit, feline IL-12 single chain, canineIL-12 p35 subunit, canine IL-12 p40 subunit, and/or canine IL-12 singlechain-containing domain. Preferred fusion segments include a metalbinding domain (e.g., a poly-histidine segment); an immunoglobulinbinding domain (e.g., Protein A; Protein G; T cell; B cell; Fc receptoror complement protein antibody-binding domains); a sugar binding domain(e.g., a maltose binding domain); and/or a “tag” domain (e.g., at leasta portion of β-galactosidase, a strep tag peptide, a T7 tag peptide, aFlag™ peptide, or other domains that can be purified using compoundsthat bind to the domain, such as monoclonal antibodies). More preferredfusion segments include metal binding domains, such as a poly-histidinesegment; a maltose binding domain; a strep tag peptide, such as thatavailable from Biometra in Tampa, Fla. and an S10 peptide.

[0050] The phrase, a nucleic acid linker, is a term known to thoseskilled in the art, and refers to a nucleic acid linker that can link,or attach, nucleic acid molecules, in such a manner that expression ofthe nucleic acid molecules produces one fusion protein as expressionproduct. A linker can be any nucleotide sequence that directs expressionof a single fusion polypeptide from a nucleotide molecule which includestwo or more nucleic acid molecules of the present invention, wherein thefusion polypeptide has appropriate biological activity. Preferably, anucleic acid linker of the present invention comprises nucleotidesarranged in codons, (i.e., 3 nucleotides that, when transcribed, codefor an amino acid residue), and the linker does not contain any stopcodons in frame. A linker is represented herein as (XXX)_(n), where X isthe designation of a variable nucleotide and n refers to the number ofcodons. The length of the nucleic acid linker may be of any length thatpermits expression of the fusion protein. More preferably, the length ofthe nucleic acid linker is from about 0 codons to about 60 codons, orfrom about 0 nucleotides to about 180 nucleotides. A particularlypreferred linker includes SEQ ID NO:83. Appropriate biological activityincludes the ability of such a fusion protein to elicit an immuneresponse against a protein of the present invention, selectively bindingan antibody raised against a protein of the present invention, andexhibiting the immunoregulatory activity of a protein of the presentinvention.

[0051] A single chain IL-12 protein of the present invention includessingle chain IL-12 proteins comprising an IL-12 p35 subunit of thepresent invention at the N-terminus of the single chain protein and anIL-12 p40 subunit of the present invention at the C-terminus of thesingle chain protein, with the linker between the p35 subunit and thep40 subunit. Preferred single chain IL-12 proteins comprise an IL-12 p40of the present invention at the N-terminus of the single chain proteinand an IL-12 p40 subunit of the present invention at the C-terminus ofthe single chain protein, with the linker in between the subunits.

[0052] Another embodiment of the present invention includes an isolatednucleic acid molecule that is selected from the group consisting of: (i)a nucleic acid molecule having a nucleic acid sequence that is at least92 percent identical to a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ IDNO:7, SEQ ID NO:10, SEQ ID NO:9, SEQ ID NO:41, SEQ ID NO:11, and SEQ IDNO:13; and (ii) a nucleic acid molecule comprising a fragment of anucleic acid molecule of (i) wherein said fragment is at least 80nucleotides in length. Preferred nucleic acid molecules include nucleicacid sequences that are at least 92%, at least 93%, at least 94%, morepreferably at least 95% identical, and even more preferably at leastabout 98% identical to SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:6, SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:9, SEQ ID NO:41, SEQ IDNO:11, and SEQ ID NO:13. Preferred fragment lengths include fragments ofSEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ IDNO:10, SEQ ID NO:9, SEQ ID NO:41, SEQ ID NO:11, and SEQ ID NO:13 whichare at least 75 nucleotides in length, which are at least 80 nucleotidesin length, which are at least 85 nucleotides in length, which are atleast 90 nucleotides in length, which are at least 100 nucleotides inlength, which are at least 120 nucleotides in length, which are at least150 nucleotides in length, which are at least 200 nucleotides in length,which are at least 300 nucleotides in length, which are at least 400nucleotides in length, which are at least 500 nucleotides in length,which are at least 600 nucleotides in length, and which preferably arefull-length.

[0053] Another embodiment of the present invention includes an isolatednucleic acid molecule that is selected from the group consisting of: (i)a nucleic acid molecule having a nucleic acid sequence that is at least85 percent identical to a nucleic acid sequence selected from the groupconsisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19,SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:25; and (ii) anucleic acid molecule comprising a fragment of a nucleic acid moleculeof (i) wherein said fragment is at least 85 nucleotides in length.Preferred nucleic acid molecules include nucleic acid sequences that areat least 85%, preferably at least 87%, more preferably at least 90%,even more preferably at least 95% identical to SEQ ID NO:14, SEQ IDNO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ IDNO:23, and SEQ ID NO:25. Preferred fragment lengths include fragments ofSEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20,SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:25 which are at least 70nucleotides in length, which are at least 80 nucleotides in length,which are at least 85 nucleotides in length, which are at least 90nucleotides in length, which are at least 100 nucleotides in length,which are at least 200 nucleotides in length, which are at least 300nucleotides in length, which are at least 400 nucleotides in length,which are at least 500 nucleotides in length, which are at least 600nucleotides in length, or which preferably are full-length.

[0054] Another embodiment of the present invention is an isolatednucleic acid molecule selected from the group consisting of: (i) anucleic acid molecule comprising (a) a nucleic acid molecule comprisinga nucleic acid sequence that is at least 87 percent identical to anucleic acid sequence selected from the group consisting of SEQ ID NO:26and SEQ ID NO:29, or a fragment thereof of at least 55 nucleotides inlength; (b) a nucleic acid linker of (XXX)_(n) wherein n=0 to 60, and(c) a nucleic acid molecule comprising a nucleic acid sequence that isat least 87 percent identical to a nucleic acid sequence selected fromthe group consisting of SEQ ID NO:32 and SEQ ID NO:35, or a fragmentthereof of at least 55 nucleotides in length, such that said nucleicacid molecule of (i) encodes a feline IL-12 single chain protein; and anucleic acid molecule fully complementary to the coding strand of anucleic acid molecule as set forth in (i). Preferred nucleic acidmolecules include nucleic acid sequences that are at least 87%, at least88%, at least 89%, more preferably at least 90%, even more preferably atleast 95% identical to SEQ ID NO:26, SEQ ID NO:29, SEQ ID NO:32, and SEQID NO:35. Preferred fragment lengths include fragments of SEQ ID NO:26,SEQ ID NO:29, SEQ ID NO:32, and SEQ ID NO:35, which are at least 55nucleotides in length, which are at least 60 nucleotides in length,which are at least about 65 nucleotides in length, which are at least 70nucleotides in length, which are at least 80 nucleotides in length,which are at least 90 nucleotides in length, which are at least 100nucleotides in length, which are at least 200 nucleotides in length,which are at least 300 nucleotides in length, which are at least 400nucleotides in length, which are at least 500 nucleotides in length,which are at least 600 nucleotides in length, or which preferably arefull-length.

[0055] Another embodiment of the present invention is an isolatednucleic acid molecule s elected from the group consisting of: (i) anucleic acid molecule comprising (a) a nucleic acid molecule comprisinga nucleic acid sequence that is at least 87 percent identical to anucleic acid sequence selected from the group consisting of SEQ ID NO:52and SEQ ID NO:58, o r a fragment thereof of at least 55 nucleotides inlength; (b) a nucleic acid linker of (XXX)_(n) wherein n=0 to 60; and(c) a nucleic acid molecule comprising a nucleic acid sequence that isat least 87 percent identical to a nucleic acid sequence selected fromthe group consisting of SEQ ID NO:46 and SEQ ID NO:49, or a fragmentthereof of at least 55 nucleotides in length, such that said nucleicacid molecule of (i) encodes a canine IL-12 single chain protein; and anucleic ac id molecule fully complementary to the coding strand of anucleic acid molecule as set forth in (i). Preferred nucleic acidmolecules include nucleic acid sequences that are at least 87%, at least88%, at least 89%, more preferably at least 90%, even more preferably atleast 95% identical to SEQ ID NO:52, SEQ ID NO:58, SEQ ID NO:46, and SEQID NO:49. Preferred fragment lengths include fragments of SEQ ID NO:52,SEQ ID NO:58, SEQ ID NO:46, and SEQ ID NO:49, which are at least 55nucleotides in length, which are at least 60 nucleotides in length,which are at least about 65 nucleotides in length, which are at least 70nucleotides in length, which are at least 80 nucleotides in length,which are at least 90 nucleotides in length, which are at least 100nucleotides in length, which are at least 200 nucleotides in length,which are at least 300 nucleotides in length, which are at least 400nucleotides in length, which are at least 500 nucleotides in length,which are at least 600 nucleotides in length, or which preferably arefull-length.

[0056] Preferred portions, or fragments, of a feline IL-18, felinecaspase-1, canine or feline IL-12 single chain protein of the presentinvention include at least 15 amino acids, at least 20 amino acids, atleast 25 amino acids, at least 30 amino acids, at least 35 amino acids,at least 40 amino acids, at least 45 amino acids, at least 50 aminoacids, at least 60 amino acids, at least 75 amino acids or at least 100amino acids. An IL-18 or IL-12 single chain protein of the presentinvention can include at least a portion of an IL-18 or IL-12 singlechain protein that is capable of binding to an IL-18 or IL-12 receptor,respectively. These receptors are known to those of skill in the art,and are described in Janeway et al., in Immunobiology, the Immune Systemin Health and Disease, Garland Publishing, Inc., NY, 1996 (which isincorporated herein by this reference in its entirety). The IL-18 orIL-12 receptor-binding portion of an IL-18 or IL-12 protein,respectively, can be determined by incubating the protein with anisolated IL-18 or IL-12 receptor, as appropriate, or a cell having anIL-18 or IL-12 receptor on its surface, as appropriate. IL-18 or IL-12protein binding to purified IL-18 or IL-12 receptor, respectively, canbe determined using methods known in the art including Biacore®screening, confocal immunofluorescent microscopy, immunoprecipitation,gel chromatography, determination of inhibition of binding of antibodiesthat bind specifically to the IL-18 or IL-12 binding domain of an IL-18or IL-12 receptor, ELISA using an IL-18 or IL-12 receptor, respectively,labeled with a detectable tag such as an enzyme or chemiluminescent tagor yeast-2 hybrid technology. A caspase-1 protein of the presentinvention can include at least a portion of a caspase-1 protein that iscapable cleaving pro-IL-18 to mature IL-18. The ability of the caspase-1protein to cleave IL-18 can be determined by methods known in the art,including methods such as Biacore® screening, confocal immunofluorescentmicroscopy, immunoprecipitation, gel chromatography, determination ofinhibition of cleavage upon binding of antibodies that bind specificallyto either IL-18 or caspase-1, and enzymatic assays.

[0057] The present invention also includes mimetopes of feline IL-18,feline caspase-1, and canine and/or feline IL-12 single chain proteinsof the present invention. As used herein, a mimetope of animmunoregulatory protein of the present invention refers to any compoundthat is able to mimic the activity of such a feline IL-18, felinecaspase-1, and canine and/or feline IL-12 single chain protein,respectively, often because the mimetope has a structure that mimics theparticular protein. Mimetopes can be, but are not limited to: peptidesthat have been modified to decrease their susceptibility to degradationsuch as all-D retro peptides; anti-idiotypic and/or catalyticantibodies, or fragments thereof; non-proteinaceous immunogenic portionsof an isolated protein (e.g., carbohydrate structures); and/or syntheticor natural organic molecules, including nucleic acids. Such mimetopescan be designed using computer-generated structures of proteins of thepresent invention. Mimetopes can also be obtained by generating randomsamples of molecules, such as oligonucleotides, peptides or otherorganic molecules, and screening such samples by affinity chromatographytechniques using the corresponding binding partner.

[0058] Furthermore, it is known in the art that there are commerciallyavailable computer programs for determining the degree of similaritybetween two nucleic acid or protein sequences. These computer programsinclude various known methods to determine the percentage identity andthe number and length of gaps between hybrid nucleic acid molecules orproteins. Preferred methods to determine the percent identity amongamino acid sequences and also among nucleic acid sequences includeanalysis using one or more of the commercially available computerprograms designed to compare and analyze nucleic acid or amino acidsequences. These computer programs include, but are not limited to, theSeqLab® Wisconsin Package™ Version 10.0-UNIX sequence analysis software,available from Genetics Computer Group, Madison, Wis.; and DNAsis®sequence analysis software, version 2.0, available from HitachiSoftware, San Bruno, Calif. Such software programs represent acollection of algorithms paired with a graphical user interface forusing the algorithms. The DNAsis version 2.0 software and SeqLabWisconsin Package Version 10.0-UNIX software, for example, employ aparticular algorithm, the Needleman-Wunsch algorithm to performpair-wise comparisons between two sequences to yield a percentageidentity score, see Needleman, S. B. and Wunsch, C. D., 1970, J. Mol.Biol., 48, 443, which is incorporated herein by reference in itsentirety. Such algorithms, including the Needleman-Wunsch algorithm, arecommonly used by those skilled in the nucleic acid and amino acidsequencing art to compare sequences. A preferred method to determinepercent identity among amino acid sequences and also among nucleic acidsequences includes using the Needleman-Wunsch algorithm, available inthe SeqLab Wisconsin Package Version 10.0-UNIX software (hereinafter“SeqLab”), using the Pairwise Comparison/Gap function with thenwsgapdna.cmp scoring matrix, the gap creation penalty and the gapextension penalties set at default values, and the gap shift limits setat maximum (hereinafter referred to as “SeqLab default parameters”). Anadditional preferred method to determine percent identity among aminoacid sequences and also among nucleic acid sequences includes using theHiggins-Sharp algorithm, available in the DNAsis version 2.0 software(hereinafter “DNAsis”), with the gap penalty set at 5, the number of topdiagonals set at 5, the fixed gap penalty set at 10, the k-tuple set at2, the window size set at 5, and the floating gap penalty set at 10. Aparticularly preferred method to determine percent identity among aminoacid sequences and also among nucleic acid sequences includes using theNeedleman-Wunsch algorithm available in the DNAsis version 2.0 software,using the GCG default parameter function.

[0059] Another embodiment of the present invention includes a nucleicacid molecule that is selected from the group consisting of: SEQ IDNO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:10,SEQ ID NO:9, SEQ ID NO:41, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14, SEQID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ IDNO:23, SEQ ID NO:25, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:43, SEQ IDNO:45, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:66, and SEQ ID NO:68, and anucleic acid molecule comprising an allelic variant of a nucleic acidmolecule comprising any of said nucleic acid sequences. An allelicvariant of a feline and/or canine nucleic acid molecule of the presentinvention, including the particular SEQ ID NO's cited herein, is a genethat occurs at essentially the same locus (or loci) in the genome as thegene including the particular SEQ ID NO's cited herein, but which, dueto natural variations caused by, for example, mutation or recombination,has a similar but not identical sequence. Also included in the termallelic variant are allelic variants of cDNAs derived from such genes.Because natural selection typically selects against alterations thataffect function, allelic variants usually encode proteins having similaractivity to that of the protein encoded by the gene to which they arebeing compared. Allelic variants of genes or nucleic acid molecules canalso comprise alterations in the 5′ or 3′ untranslated regions of thegene (e.g., in regulatory control regions), or can involve alternativesplicing of a nascent transcript, thereby bringing alternative exonsinto juxtaposition. Allelic variants are well known to those skilled inthe art and would be expected to be found within a given animal, sincethe respective genomes are diploid, and sexual reproduction will resultin the reassortment of alleles. As such, a nucleic acid molecule of thepresent invention can be an allelic variant that includes a similar butnot identical sequence to SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:6, SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:9, SEQ ID NO:41, SEQ IDNO:11, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:17, SEQ IDNO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:25, SEQ IDNO:38, SEQ ID NO:40, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:61, SEQ IDNO:63, SEQ ID NO:66, and SEQ ID NO:68, and/or any other nucleic acidmolecule cited herein.

[0060] In another embodiment of the present invention, a nucleic acidmolecule of the invention is selected from the group consisting of (a) anucleic acid molecule comprising a nucleic acid sequence that encodes aprotein having an amino acid sequence selected from the group consistingof SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:15,SEQ ID NO:18, SEQ ID NO:21, SEQ ID NO:24, SEQ ID

[0061] NO:39, SEQ ID NO:44, SEQ ID NO:62, and SEQ ID NO:67, and b) anucleic acid molecule comprising an allelic variant of a nucleic acidmolecule encoding a protein having any of said amino acid sequences of(a).

[0062] Another embodiment of the present invention includes feline IL-18nucleic acid molecules of the present invention, wherein said nucleicacid molecules encode a protein having a function selected from thegroup consisting of (i) eliciting an immune response against an IL-18protein having an amino acid sequence selected from the group consistingof SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ ID NO:12; (ii)selectively binding to an antibody raised against an IL-18 proteinhaving an amino acid sequence selected from the group consisting of SEQID NO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ ID NO:12, and (iii)exhibiting IL-18 activity. Methods to elicit an immune response and todetermine whether an antibody can selectively bind to a particularprotein or antigen are known in the art, see, for example, Harlow, etal. (1988) Antibodies, a Laboratory Manual, Cold Spring Harbor LabsPress; Harlow, et al. is incorporated by reference herein in itsentirety. Methods to determine whether an IL-18 protein has IL-18activity are known in the art, and include determining whether IL-18 hasthe activity of stimulating T cells to produce interferon gamma (IFN-γ).

[0063] Another embodiment of the present invention includes caspase-1nucleic acid molecules of the present invention that encode a proteinhaving a function selected from the group consisting of (i) eliciting animmune response against a caspase-1 protein having an amino acidsequence selected from the group consisting of SEQ ID NO:15, SEQ IDNO:18, SEQ ID NO:21, and SEQ ID NO:24, (ii) selectively binding to anantibody raised against caspase-1 protein having an amino acid sequenceselected from the group consisting of SEQ ID NO:15, SEQ ID NO:18, SEQ IDNO:21, and SEQ ID NO:24, and (iii) exhibiting caspase-1 activity.Methods to elicit an immune response and to determine whether anantibody can selectively bind to a particular protein or antigen areknown in the art, see, for example, Harlow, et al. (1988) Antibodies, aLaboratory Manual, Cold Spring Harbor Labs Press; Harlow, et al. isincorporated by reference herein in its entirety. Methods to determinewhether a caspase-1 protein has caspase-1 activity are known in the art,and include, for example, determining if the caspase-1 protein has theability to cleave the precursor form of IL-18 resulting in abiologically active IL-18.

[0064] Another embodiment of the present invention includes canine andfeline IL-12 single chain nucleic acid molecules of the presentinvention, wherein a said nucleic acid molecule encodes a protein havinga function selected from the group consisting of (i) eliciting an immuneresponse against an IL-12 protein having an amino acid selected from thegroup consisting of SEQ ID NO:39, SEQ ID NO:44, SEQ ID NO:62, and SEQ IDNO:67, (ii) selectively binding to an antibody raised against an IL-12protein having an amino acid sequence selected from the group consistingfrom the group of SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, SEQ IDNO:36, SEQ ID NO:47, SEQ ID NO:50, SEQ ID NO:53, and SEQ ID NO:59, SEQID NO:102, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:39, SEQ ID NO:40, SEQID NO:62, and/or SEQ ID NO:67, and (iii) exhibiting IL-12 activity.Methods to elicit an immune response and to determine whether anantibody can selectively bind to a particular protein or antigen areknown in the art, see, for example, Harlow, et al. (1988) Antibodies, aLaboratory Manual, Cold Spring Harbor Labs Press; Harlow, et al. isincorporated by reference herein in its entirety. Methods to determinewhether an IL-12 protein has IL-12 activity are known in the art, andinclude determining if IL-12 has the activity of stimulating T cells toproduce interferon gamma (IFN-γ).

[0065] A preferred nucleic acid molecule of the present inventionincludes a nucleic acid molecule selected from the group consisting ofnFeIL-12p40-N₉₈₅, nFeIL-12p40₉₈₇, nFeIL-12p40₉₂₁, nFeIL-12p35₆₆₆,nFeIL-12p35-N₅₆₁, nFeIL-12p35₅₉₁, nCaIL-12p35₆₆₆, nCaIL-12p35₁₄₅₅,nCaIL-12p35₅₉₁, nCaIL-12p40₂₂₆₇, nCaIL-12p40₉₂₁, nCaIL-12p40₉₈,nFeIL-12₁₅₉₉, nFeIL-12₁₅₃₃, nCaIL-12₁₅₉₉, and nCaIL-12₁₅₃₃.

[0066] Another embodiment of the present invention includes an isolatednucleic acid molecule selected from the group consisting of: a nucleicacid molecule having a nucleic acid sequence encoding an IL-18 proteinselected from the group consisting of: a protein selected from the groupconsisting of (a) a protein having an amino acid sequence that is atleast 92 percent identical to an amino acid sequence selected from thegroup consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ IDNO:12, and (b) a protein comprising a fragment of a protein of (a),wherein said fragment is at least 30 amino acids in length; and aprotein comprising at least 25 contiguous amino acids identical insequence to at least 25 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8, and SEQ ID NO:12. Preferred IL-18 proteins include proteins thatare at least about 90 percent identical, preferably at least about 92percent identical, preferably at least about 94 percent identical,preferably at least about 96 percent identical, and even more preferablyat least about 98 percent identical to SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8, and SEQ ID NO:12 or fragments thereof. Preferred fragments ofIL-18 proteins include fragments of SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8, and SEQ ID NO:12 that are at least about 20 amino acids in length,at least about 30 amino acids in length, at least about 40 amino acidsin length, at least about 50 amino acids in length, preferably at leastabout 75 amino acids in length, preferably at least about 100 aminoacids in length, and more preferably are full-length. Preferred IL-18proteins also include proteins that comprise at least 15 contiguousamino acids identical in sequence to at least 15 contiguous amino acids;at least 20 contiguous amino acids identical in sequence to at least 20contiguous amino acids, preferably about 30 contiguous amino acidsidentical in sequence to at least 30 contiguous amino acids, preferablyabout 50 contiguous amino acids identical in sequence to at least 50contiguous amino acids, preferably about 75 contiguous amino acidsidentical in sequence to at least 75 contiguous amino acids, preferablyabout 100 contiguous amino acids identical in sequence to at least 100contiguous amino acids, and most preferably a full-length proteinidentical in sequence to a full-length protein of an amino acid sequenceselected from the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8, and SEQ ID NO:12.

[0067] Another embodiment of the present invention includes an isolatednucleic acid molecule selected from the group consisting of: a nucleicacid molecule having a nucleic acid sequence encoding caspase proteinselected from the group consisting of: a protein selected from the groupconsisting of (a) a protein having an amino acid sequence that is atleast 85 percent identical to an amino acid sequence selected from thegroup consisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ IDNO:24, and (b) a protein comprising a fragment of a protein of (a),wherein said fragment is at least 30 amino acids in length; and aprotein comprising at least 25 contiguous amino acids identical insequence to at least 25 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8, and SEQ ID NO:12. Preferred caspase-1 proteins include proteinsthat are at least about 85 percent identical, at least about 87 percentidentical, preferably at least about 90 percent identical, preferably atleast about 93 percent identical, more preferably at least about 95percent identical, and even more preferably about 98 percent identicalto SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24 orfragments thereof. Preferred fragments of caspase-1 proteins includefragments of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24include fragments that are at least about 20 amino acids in length, atleast about 30 amino acids in length, at least about 40 amino acids inlength, at least about 50 amino acids in length, at least about 60 aminoacids in length, preferably at least about 75 amino acids in length,preferably at least about 100 amino acids in length, and more preferablyare full-length. Preferred caspase-1 proteins also include proteins thatcomprise at least 25 contiguous amino acids identical in sequence to atleast 25 contiguous amino acids; at least 20 contiguous amino acidsidentical in sequence to at least 20 contiguous amino acids, preferablyabout 30 contiguous amino acids identical in sequence to at least 30contiguous amino acids, preferably about 50 contiguous amino acidsidentical in sequence to at least 50 contiguous amino acids, preferablyabout 75 contiguous amino acids identical in sequence to at least 75contiguous amino acids, preferably about 100 contiguous amino acidsidentical in sequence to at least 100 contiguous amino acids, and mostpreferably a full-length protein identical in sequence to a full-lengthprotein of an amino acid sequence selected from the group consisting ofSEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24.

[0068] Another embodiment of the present invention includes a nucleicacid molecule having a nucleic acid sequence encoding an IL-12 singlechain protein comprising an IL-12 p40 subunit domain linked to a IL-12p35 subunit domain, wherein said p40 subunit domain is selected from thegroup consisting of: (i) a p40 subunit protein having an amino acidsequence that is at least 84 percent identical to an amino acid sequenceselected from the group consisting of SEQ ID NO:27 and SEQ ID NO:30,(ii) a p40 subunit protein comprising a fragment of a protein of (i),wherein said fragment is at least 30 amino acids in length, and (iii) ap40 subunit protein comprising at least 23 contiguous amino acidsidentical in sequence to at least 23 contiguous amino acids of an aminoacid sequence selected from the group consisting of SEQ ID NO:27 and SEQID NO:30, and wherein said p35 domain is selected from the groupconsisting of (i) a p35 subunit protein having an amino acid sequencethat is at least 84 percent identical to an amino acid sequence selectedfrom the group consisting of SEQ ID NO:33 and SEQ ID NO:36, (ii) a p35subunit protein comprising a fragment of a protein of (i), wherein saidfragment is at least 30 amino acids in length, and (iii) a p35 subunitprotein comprising at least 23 contiguous amino acids identical insequence to at least 23 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:33 and SEQ ID NO:36.Preferred p40 subunit proteins and/or p35 subunit proteins includeproteins that are at least about 84 percent identical, preferably atleast about 87 percent identical, preferably at least about 90 percentidentical, and even more preferably at least about 95 percent identicalto SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, and SEQ ID NO:36 orfragments thereof. Preferred fragments of IL-12 single chain proteinsinclude fragments of SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, and SEQID NO:36 include fragments that are at least about 30 amino acids inlength, at least about 40 amino acids in length, at least about 50 aminoacids in length, at least about 60 amino acids in length, preferably atleast about 75 amino acids in length, preferably at least about 100amino acids in length, and more preferably are full-length. PreferredIL-12 single chain proteins also include proteins that comprise at least23 contiguous amino acids identical in sequence to at least 23contiguous amino acids, preferably about 30 contiguous amino acidsidentical in sequence to at least 30 contiguous amino acids, preferablyabout 50 contiguous amino acids identical in sequence to at least 50contiguous amino acids, preferably about 75 contiguous amino acidsidentical in sequence to at least 75 contiguous amino acids, preferablyabout 100 contiguous amino acids identical in sequence to at least 100contiguous amino acids, and most preferably a full-length proteinidentical in sequence to a full-length protein of an amino acid sequenceselected from the group consisting of SEQ ID NO:27, SEQ ID NO:30, SEQ IDNO:33, and SEQ ID NO:36.

[0069] Another embodiment of the present invention includes a nucleicacid molecule having a nucleic acid sequence encoding an IL-12 singlechain protein comprising an IL-12 p40 subunit domain linked to a IL-12p35 subunit domain, wherein said p40 subunit domain is selected from thegroup consisting of: (i) a p40 subunit protein having an amino acidsequence that is at least 84 percent identical to an amino acid sequenceselected from the group consisting of SEQ ID NO:53 and SEQ ID NO:59,(ii) a p40 subunit protein comprising a fragment of a protein of (i),wherein said fragment is at least 40 amino acids in length, and (iii) ap40 subunit protein comprising at least 31 contiguous amino acidsidentical in sequence to at least 31 contiguous amino acids of an aminoacid sequence selected from the group consisting of SEQ ID NO:53 and SEQID NO:59, and wherein said p35 domain is selected from the groupconsisting of (i) a p35 subunit protein having an amino acid sequencethat is at least 84 percent identical to an amino acid sequence selectedfrom the group consisting of SEQ ID NO:47 and SEQ ID NO:50, (ii) a p35subunit protein comprising a fragment of a protein of (i), wherein saidfragment is at least 40 amino acids in length, and (iii) a p35 subunitprotein comprising at least 31 contiguous amino acids identical insequence to at least 31 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:47 and SEQ ID NO:50.Preferred p40 subunit proteins and/or p35 subunit proteins includeproteins that are at least about 84 percent identical, preferably atleast about 87 percent identical, preferably at least about 90 percentidentical, and even more preferably at least about 95 percent identicalto SEQ ID NO:47, SEQ ID NO:50, SEQ ID NO:53, and SEQ ID NO:59 orfragments thereof. Preferred fragments of IL-12 single chain proteinsinclude fragments of SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, and SEQID NO:36 include fragments that are at least about 40 amino acids inlength, at least about 50 amino acids in length, at least about 60 aminoacids in length, at least about 70 amino acids in length, preferably atleast about 80 amino acids in length, preferably at least about 100amino acids in length, and more preferably are full-length. PreferredIL-12 single chain proteins also include proteins that comprise at least31 contiguous amino acids identical in sequence to at least 31contiguous amino acids, preferably about 35 contiguous amino acidsidentical in sequence to at least 35 contiguous amino acids, preferablyabout 50 contiguous amino acids identical in sequence to at least 50contiguous amino acids, preferably about 75 contiguous amino acidsidentical in sequence to at least 75 contiguous amino acids, preferablyabout 100 contiguous amino acids identical in sequence to at least 100contiguous amino acids, and most preferably a full-length proteinidentical in sequence to a full-length protein of an amino acid sequenceselected from the group consisting of SEQ ID NO:47, SEQ ID NO:50, SEQ IDNO:53, and SEQ ID NO:59.

[0070] Another embodiment of the present invention includes a nucleicacid molecule comprising a nucleic acid sequence fully complementary tothe coding strand of any of the nucleic acid molecules of the presentinvention. Another embodiment of the present invention includes anucleic acid molecule that comprises a nucleic acid sequence thatencodes a protein selected from the group consisting of an IL-18protein, a caspase-1 protein, and an IL-12 single chain protein.

[0071] Another embodiment of the present invention includes a nucleicacid molecule that is selected from the group consisting of a nucleicacid molecule comprising a nucleic acid sequence encoding a proteincomprising an amino acid sequence selected from the group consisting ofSEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:15, SEQID NO;18, SEQ ID NO:21, SEQ ID NO:24, SEQ ID NO:39, SEQ ID NO:44, SEQ IDNO:62, and SEQ ID NO:67; and a nucleic acid molecule comprising anallelic variant of a nucleic acid molecule encoding a protein having anyof said nucleic acid molecules set forth in this paragraph. In anotherembodiment, a nucleic acid molecule encoding an IL-12 single chainprotein of the present invention further comprises a nucleic acidmolecule encoding a linker.

[0072] The present invention also includes oligonucleotides, recombinantmolecules, recombinant viruses and recombinant cells comprising suchnucleic acid molecules and methods to produce such nucleic acidmolecules, oligonucleotides, recombinant molecules, recombinant virusesand recombinant cells.

[0073] Knowing the nucleic acid sequences of certain nucleic acidmolecules of the present invention allows one skilled in the art to, forexample, (a) make copies of those nucleic acid molecules, (b) obtainnucleic acid molecules including at least a portion of such nucleic acidmolecules, e.g., nucleic acid molecules including full-length genes,full-length coding regions, regulatory control sequences, truncatedcoding regions, and (c) obtain other nucleic acid molecules. Suchnucleic acid molecules can be obtained in a variety of ways includingscreening appropriate expression libraries with antibodies of thepresent invention; traditional cloning techniques using oligonucleotideprobes of the present invention to screen appropriate libraries; and PCRamplification of appropriate libraries or DNA using oligonucleotideprimers of the present invention. A preferred library to screen or fromwhich to amplify nucleic acid molecules is a feline or canine mastlibrary or a feline or canine peripheral blood mononuclear cell library.Techniques to clone and amplify genes are disclosed, for example, inSambrook et al., ibid.

[0074] Oligonucleotides of the present invention can be RNA, DNA, orderivatives of either. The minimum size of such oligonucleotides is thesize required for formation of a stable hybrid between anoligonucleotide and a complementary sequence on a larger nucleic acidmolecule of the present invention, typically from about 12 to 15 toabout 17 to 18 nucleotides depending on the GC/AT content. The presentinvention includes oligonucleotides that can be used as, for example,probes to identify nucleic acid molecules, primers to produce nucleicacid molecules, or therapeutic reagents to inhibit protein production oractivity, e.g., as antisense-, triplex formation-, ribozyme- and/or RNAdrug-based reagents. The present invention also includes the use of sucholigonucleotides to protect animals from disease using one or more ofsuch technologies. Appropriate oligonucleotide-containing therapeuticcompositions can be administered to an animal using techniques known tothose skilled in the art.

[0075] One embodiment of the present invention includes a recombinantvector, which includes at least one isolated nucleic acid molecule ofthe present invention, inserted into any vector capable of deliveringthe nucleic acid molecule into a host cell. Such a vector containsheterologous nucleic acid sequences, that is nucleic acid sequences thatare not naturally found adjacent to nucleic acid molecules of thepresent invention and that preferably are derived from a species otherthan the species from which the nucleic acid molecule(s) are derived.The vector can be either RNA or DNA, either prokaryotic or eukaryotic,and typically is a virus or a plasmid. Recombinant vectors can be usedin the cloning, sequencing, and/or otherwise manipulating of the nucleicacid molecules of the present invention.

[0076] One type of recombinant vector, referred to herein as arecombinant molecule, comprises a nucleic acid molecule of the presentinvention operatively linked to an expression vector. The phraseoperatively linked refers to insertion of a nucleic acid molecule intoan expression vector in a manner such that the nucleic acid molecule isable to be expressed when transformed into a host cell. As used herein,an expression vector is a DNA or RNA vector that is capable oftransforming a host cell and of effecting expression of a specifiednucleic acid molecule. Preferably, the expression vector is also capableof replicating within the host cell. Expression vectors can be eitherprokaryotic or eukaryotic, and are typically viruses or plasmids.Expression vectors of the present invention include any vectors thatfunction, i.e., direct gene expression, in recombinant cells of thepresent invention, including in bacterial, fungal, insect, other animal,and plant cells. Preferred expression vectors of the present inventioncan direct gene expression in bacterial, yeast, insect and mammaliancells, and more preferably in the cell types disclosed herein.

[0077] In particular, expression vectors of the present inventioncontain regulatory sequences such as transcription control sequences,translation control sequences, origins of replication, and otherregulatory sequences that are compatible with the recombinant cell andthat control the expression of nucleic acid molecules of the presentinvention. In particular, recombinant molecules of the present inventioninclude transcription control sequences. Transcription control sequencesare sequences that control the initiation, elongation, and terminationof transcription. Particularly important transcription control sequencesare those that control transcription initiation, such as promoter,enhancer, operator and repressor sequences. Suitable transcriptioncontrol sequences include any transcription control sequence that canfunction in at least one of the recombinant cells of the presentinvention. A variety of such transcription control sequences are knownto those skilled in the art. Preferred transcription control sequencesinclude those which function in bacterial, yeast, or insect andmammalian cells, such as, but not limited to, tac, lac, trp, trc,oxy-pro, omp/lpp, rrnB, bacteriophage lambda, such as lambda p_(L) andlambda p_(R) and fusions that include such promoters, bacteriophage T7,T7lac, bacteriophage T3, bacteriophage SP6, bacteriophage SP01,metallothionein, alpha-mating factor, Pichia alcohol oxidase, alphavirussubgenomic promoter, antibiotic resistance gene, baculovirus, Heliothiszea insect virus, vaccinia virus, herpesvirus, raccoon poxvirus, otherpoxvirus, adenovirus, cytomegalovirus, such as immediate early promoter,simian virus 40, retrovirus, actin, retroviral long terminal repeat,Rous sarcoma virus, heat shock, phosphate and nitrate transcriptioncontrol sequences as well as other sequences capable of controlling geneexpression in prokaryotic or eukaryotic cells. Additional suitabletranscription control sequences include tissue-specific promoters andenhancers as well as lymphokine-inducible promoters, e.g., promotersinducible by interferons or interleukins.

[0078] A recombinant cell of the present invention includes any celltransformed with at least one of any nucleic acid molecule of thepresent invention. Suitable and preferred nucleic acid molecules as wellas suitable and preferred recombinant molecules with which to transfercells are disclosed herein. A recombinant cell is preferably produced bytransforming a host cell with one or more recombinant molecules, eachcomprising one or more nucleic acid molecules of the present inventionoperatively linked to an expression vector containing one or moretranscription control sequences, examples of which are disclosed herein.

[0079] Transformation of a nucleic acid molecule into a cell can beaccomplished by any method by which a nucleic acid molecule can beinserted into the cell. Transformation techniques include, but are notlimited to, transfection, electroporation, microinjection, lipofection,adsorption, and protoplast fusion. A recombinant cell may remainunicellular or may grow into a tissue, organ or a multicellularorganism. It is to be noted that a cell line refers to any recombinantcell of the present invention that is not a transgenic animal.Transformed nucleic acid molecules of the present invention can remainextrachromosomal or can integrate into one or more sites within achromosome of the transformed, i.e., recombinant, cell in such a mannerthat their ability to be expressed is retained. Preferred nucleic acidmolecules with which to transform a cell include nucleic acid moleculesdisclosed herein. Particularly preferred nucleic acid molecules withwhich to transform a cell include nFeIL-18-N₅₁₄, nFeIL-18-C₅₀₂,nFeIL-18₆₀₇, nFeIL-18₅₇₆, nFeIL-18₄₇₁, nFeCasp-1₁₂₃₃, nFeCasp-1-N₅₂₆,nFeCasp-1-C₅₀₀, nFeCasp-1₁₂₃₀, nFeIL-12p40-N₉₈₅, nFeIL-12p40₉₈₇,nFeIL-12p40₉₂₁, nFeIL-12p35₆₆₆, nFeIL-12p35-N₅₆₁, nFeIL-12p35₅₉₁,nCaIL-12p35₆₆₆, nCaIL-12p35₁₄₅₅, nCaIL 12p35₅₉₁, nCaIL-12p40₂₂₆₇,nCaIL-12p40₉₂₁, and nCaIL-12p40₉₈₇, nCaIL-12₁₅₉₉, nCaIL-12₁₅₃₃,nFeIL-12₁₅₉₉, and nFeIL-12₁₅₃₃,

[0080] Recombinant molecules of the present invention may also (a)contain secretory signals, i.e., signal segment nucleic acid sequences,to enable an expressed protein of the present invention to be secretedfrom the cell that produces the protein and/or (b) contain fusionsequences which lead to the expression of nucleic acid molecules of thepresent invention as fusion proteins. Examples of suitable signalsegments include any signal segment capable of directing the secretionof a protein of the present invention. Preferred signal segmentsinclude, but are not limited to, tissue plasminogen activator (t-PA),interferon, interleukin, growth hormone, histocompatibility and viralenvelope glycoprotein signal segments. Suitable fusion segments encodedby fusion segment nucleic acids are disclosed herein. In addition, anucleic acid molecule of the present invention can be joined to a fusionsegment that directs the encoded protein to the proteosome, such as aubiquitin fusion segment. Eukaryotic recombinant molecules may alsoinclude intervening and/or untranslated sequences surrounding and/orwithin the nucleic acid sequences of nucleic acid molecules of thepresent invention.

[0081] Suitable host cells to transform include any cell that can betransformed with a nucleic acid molecule of the present invention. Hostcells can be either untransformed cells or cells that are alreadytransformed with at least one nucleic acid molecule, e.g., nucleic acidmolecules encoding one or more proteins of the present invention and/orother proteins. Host cells of the present invention either can beendogenously, i.e., naturally, capable of producing proteins of thepresent invention or can be capable of producing such proteins afterbeing transformed with at least one nucleic acid molecule of the presentinvention. Host cells of the present invention can be any cell capableof producing at least one protein of the present invention, and includebacterial, fungal, including yeast, insect, and other animal and plantcells. Preferred host cells include bacterial, mycobacterial, yeast,insect and mammalian cells. More preferred host cells includeSalmonella, Escherichia, Bacillus, Listeria, Saccharomyces, Pichia,Spodoptera, Mycobacteria, Trichoplusia, BHK (baby hamster kidney) cells,MDCK cells (Madin-Darby canine kidney cell line), CRFK cells (Crandellfeline kidney cell line), CV-1 cells (African monkey kidney cell lineused, for example, to culture raccoon poxvirus), COS (e.g., COS-7)cells, and Vero cells. Particularly preferred host cells are Escherichiacoli, including E. coli K-12 derivatives; Salmonella typhi; Salmonellatyphimurium, including attenuated strains such as UK-1 _(x)3987 andSR-11 _(x)4072; Pichia; Spodopterafrugiperda; Trichoplusia ni; BHKcells; MDCK cells; CRFK cells; CV-1 cells; COS cells; Vero cells; andnon-tumorigenic mouse myoblast G8 cells (e.g., ATCC CRL 1246).Additional appropriate mammalian cell hosts include other kidney celllines, other fibroblast cell lines, e.g., human, murine or chickenembryo fibroblast cell lines, myeloma cell lines, Chinese hamster ovarycells, mouse NIH/3T3 cells, LMTK³¹ cells and/or HeLa cells.

[0082] Recombinant cells of the present invention can also beco-transformed with one or more recombinant molecules including IL-18,caspase-1, IL-12 single chain nucleic acid molecules encoding one ormore proteins of the present invention and one or more other nucleicacid molecules encoding other compounds.

[0083] Recombinant DNA technologies can be used to improve expression oftransformed nucleic acid molecules by manipulating, for example, thenumber of copies of the nucleic acid molecules within a host cell, theefficiency with which those nucleic acid molecules are transcribed, theefficiency with which the resultant transcripts are translated, and theefficiency of post-translational modifications. Recombinant techniquesuseful for increasing the expression of nucleic acid molecules of thepresent invention include, but are not limited to, operatively linkingnucleic acid molecules to high-copy number plasmids, integration of thenucleic acid molecules into one or more host cell chromosomes, additionof vector stability sequences to plasmids, substitutions ormodifications of transcription control signals, e.g., promoters,operators, enhancers, substitutions or modifications of translationalcontrol signals, e.g., ribosome binding sites, Shine-Dalgarno sequences,modification of nucleic acid molecules of the present invention tocorrespond to the codon usage of the host cell, deletion of sequencesthat destabilize transcripts, and use of control signals that temporallyseparate recombinant cell growth from recombinant enzyme productionduring fermentation. The activity of an expressed recombinant protein ofthe present invention may be improved by fragmenting, modifying, orderivatizing nucleic acid molecules encoding such a protein.

[0084] Isolated feline IL-18, feline caspase-1, feline and/or canineIL-12 single chain proteins of the present invention can be produced ina variety of ways, including production and recovery of naturalproteins, production and recovery of recombinant proteins, and chemicalsynthesis of the proteins. In one embodiment, an isolated protein of thepresent invention is produced by culturing a cell capable of expressingthe protein under conditions effective to produce the protein, andrecovering the protein. A preferred cell to culture is a recombinantcell of the present invention. Effective culture conditions include, butare not limited to, effective media, bioreactor, temperature, pH andoxygen conditions that permit protein production. An effective mediumrefers to any medium in which a cell is cultured to produce a protein ofthe present invention. Such a medium typically comprises an aqueousmedium having assimilable carbon, nitrogen and phosphate sources, andappropriate salts, minerals, metals and other nutrients, such asvitamins. Cells of the present invention can be cultured in conventionalfermentation bioreactors, shake flasks, test tubes, microtiter dishes,and petri plates. Culturing can be carried out at a temperature, pH andoxygen content appropriate for a recombinant cell. Such culturingconditions are within the expertise of one of ordinary skill in the art.Examples of suitable conditions are included in the Examples section.

[0085] Depending on the vector and host system used for production,resultant proteins of the present invention may either remain within therecombinant cell; be secreted into the fermentation medium; be secretedinto a space between two cellular membranes, such as the periplasmicspace in E. coli; or be retained on the outer surface of a cell or viralmembrane. The phrase recovering the protein, as well as similar phrases,refers to collecting the whole fermentation medium containing theprotein and need not imply additional steps of separation orpurification. Proteins of the present invention can be purified using avariety of standard protein purification techniques, such as, but notlimited to, affinity chromatography, ion exchange chromatography,filtration, electrophoresis, hydrophobic interaction chromatography, gelfiltration chromatography, reverse phase chromatography, concanavalin Achromatography, chromatofocusing and differential solubilization.Proteins of the present invention are preferably retrieved insubstantially pure form. As used herein, substantially pure refers to apurity that allows for the effective use of the protein as a therapeuticcomposition or diagnostic. A therapeutic composition for animals, forexample, should exhibit no substantial toxicity.

[0086] The present invention also includes isolated, i.e., removed fromtheir natural milieu, antibodies that selectively bind to proteins ofthe present invention or a mimetope thereof, e.g., anti-feline IL-18,feline caspase-1, feline and canine IL-12 single antibodies. As usedherein, the term selectively binds to a protein refers to the ability ofantibodies of the present invention to preferentially bind to specifiedproteins and mimetopes thereof of the present invention. Binding can bemeasured using a variety of methods standard in the art including enzymeimmunoassays, e.g., ELISA, immunoblot assays, etc.; see, for example,Sambrook et al., ibid., and Harlow, et al., 1988, Antibodies, aLaboratory Manual, Cold Spring Harbor Labs Press; Harlow et al., ibid.,is incorporated herein by reference in its entirety. For example, ananti-feline IL-18 antibody of the present invention preferablyselectively binds to a feline IL-18 protein in such a way as to inhibitthe function of that protein.

[0087] The antibodies of the present invention bind to the proteins ofthe present invention, but not to similar proteins of other species. Forinstance, the antibodies that specifically bind feline IL-18 do not bindcanine IL-18.

[0088] Isolated antibodies of the present invention can includeantibodies in serum, or antibodies that have been purified to varyingdegrees. Antibodies of the present invention can be polyclonal ormonoclonal, or can be functional equivalents such as antibody fragmentsand genetically-engineered antibodies, including single chain antibodiesor chimeric antibodies that can bind to one or more epitopes.

[0089] A preferred method to produce antibodies of the present inventionincludes (a) administering to an animal an effective amount of aprotein, peptide or mimetope of the present invention to produce theantibodies and (b) recovering the antibodies. In another method,antibodies of the present invention are produced recombinantly usingtechniques as heretofore disclosed to produce proteins of the presentinvention. Antibodies raised against defined proteins or mimetopes canbe advantageous because such antibodies are not substantiallycontaminated with antibodies against other substances that mightotherwise cause interference in a diagnostic assay or side effects ifused in a therapeutic composition.

[0090] Antibodies of the present invention have a variety of potentialuses that are within the scope of the present invention. For example,such antibodies can be used (a) to evaluate the immune status in felidsand canids with diseases such as allergy, cancer and pathogeninfections. Furthermore, antibodies of the present invention can be usedto target cytotoxic agents to cells. Targeting can be accomplished byconjugating, i.e., stably joining, such antibodies to the cytotoxicagents using techniques known to those skilled in the art. Suitablecytotoxic agents are known to those skilled in the art. Furthermore,antibodies of the present invention can be used to detect for example,feline IL-18, caspase-1, canine IL-12 single chain, and/or feline IL-12single chain in a putative IL-18, caspase-1, canine IL-12 single chain,and/or feline IL-12 single chain containing biological sample, bycontacting the putative IL-18, caspase-1, canine IL-12 single chain,and/or feline IL-12 single chain containing biological sample with theappropriate anti-IL-18, caspase-1, canine IL-12 single chain, and/orfeline IL-12 single chain antibodies under conditions suitable forformation of an antigen-antibody complex, and then detecting saidcomplex. Methods to detect said method are known to those skilled in theart and are contained herein.

[0091] The present invention includes proteins comprising SEQ ID NO:2,SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:15, SEQ ID NO:18, SEQID NO:21, SEQ ID NO:24, SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, SEQ IDNO:36, SEQ ID NO:39, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:50, SEQ IDNO:53, SEQ ID NO:59, SEQ ID NO:62, and SEQ ID NO:67 as well as nucleicacid molecules encoding such proteins.

[0092] Preferred feline IL-18 proteins of the present invention includePFeIL-18-N₁₃₃, PFeIL-18-C₁₅₄, PFeIL-18₁₉₂, and/or PFeIL-18₁₅₇. In oneembodiment, a preferred feline IL-18 protein of the present inventionhas an amino acid sequence that includes SEQ ID NO:2, SEQ ED NO:5, SEQID NO:8, and/or SEQ ID NO:12 and is preferably encoded by a nucleic acidmolecule having nucleic acid sequences SEQ ID NO:1, SEQ ID NO:4, SEQ IDNO:7, SEQ ID NO:9 and/or SEQ ID NO:11. Such proteins are preferablyencoded by a nucleic acid molecule comprising nFeIL-18-N₅₁₄,nFeIL-18-C₅₀₂, nFeIL-18₆₀₇, nFeIL-18₅₇₆, and/or nFeIL-18₄₇₁.

[0093] Preferred feline caspase-1 proteins of the present inventioninclude proteins encoded by a nucleic acid molecule comprisingnFeCasp-1₁₂₃₃, nFeCasp-1-N₅₂₆, nFeCasp-1-C₅₀₀, and/or nFeCasp-1₁₂₃₀.Preferred feline caspase-1 proteins are PFeCasp-1₄₁₀, PFeCasp-1-N₁₆₉,and/or PFeCasp-1-C₁₂₀. In one embodiment, a preferred feline caspase-1protein of the present invention is encoded by SEQ ID NO:14, SEQ IDNO:17, SEQ ID NO:20, and/or SEQ ID NO:23, and, as such, has an aminoacid sequence that includes SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21and/or SEQ ID NO:24.

[0094] Preferred canine and feline IL-12 proteins of the presentinvention include proteins encoded by a nucleic acid molecule comprisingnFeIL-12₁₅₉₉, nFeIL-12₁₅₃₃, nCaIL-12₁₅₉₉, and/or nCaIL-12₁₅₃₃. Preferredfeline and canine IL-12 proteins are nFeIL-12p40-N₉₈₅, nFeIL-12p40₉₈₇,nFeIL-12p40₉₂₁, nFeIL-12p35₆₆₆, nFeIL-12p35-N₅₆₁, nFeIL-12p35₅₉₁,nCaIL-12p35₆₆₆, nCaIL-12p35₁₄₅₅, nCaIL-12p35₅₉₁, nCaIL-12p40₂₂₆₇,nCaIL-12p40₉₂₁, and nCaIL-12p40₉₈₇. In one embodiment, a preferredcanine and feline IL-12 single chain protein of the present invention isencoded by SEQ ID NO:38, SEQ ID NO:43, SEQ ID NO:61, and/or SEQ IDNO:66, and, as such, has an amino acid sequence that includes SEQ IDNO:39, SEQ ID NO:44, SEQ ID NO:62, and/or SEQ ID NO:67.

[0095] More preferred canine and feline IL-12 single chain proteins ofthe present invention include proteins encoded by a nucleic acidmolecule comprising nFeIL-12p40-N₉₈₅, nFeIL-12p40₉₈₇, nFeIL-12p40₉₂₁,nFeIL-12p35₆₆₆, nFeIL-12p35-N₅₆₁, nFeIL-12p35₅₉₁, nCaIL-12p35₆₆₆,nCaIL-12p35₁₄₅₅, nCaIL-12p35₅₉₁, nCaIL-12p40₂₂₆₇, nCaIL-12p40₉₂₁,nCaIL-12p40₉₈₇, nCaIL-12₁₅₃₃, nCaIL-12₁₅₉₉, nFeIL-12₁₅₃₃, andnFeIL-12₁₅₉₉. Preferred feline and canine IL-12 single chain proteinscomprise PFeIL-12p40-N₃₂₈, PFeIL-12p40₃₂₉, PFeIL-12p40₃₀₇, PFeIL12p35₂₂₂, PFeIL-12p35-N₁₈₇, PFeIL-12p35₁₉₇, PCaIL-12p35₂₂₂,PCaIL-12p35₁₉₇, PCaIL-12p40₃₀₇, PCaIL-12p40₃₂₉, PFeIL-12₅₃₃,PFeIL-12₅₁₁, PCaIL-12₅₃₃, and PCaIL-12₅₁₁. In one embodiment, apreferred canine and feline IL-12 single chain protein of the presentinvention is encoded by a nucleic acid comprising SEQ ID NO:28, SEQ IDNO:31, SEQ ID NO:32, SEQ ID NO:35, SEQ ID NO:46, SEQ ID NO:49, SEQ IDNO:52, SEQ ID NO:55, SEQ ID NO:58, SEQ ID NO:101, SEQ ID NO:104, SEQ IDNO:107, SEQ ID NO:38, SEQ ID NO:43, SEQ ID NO:61, SEQ ID NO:66, and, assuch, has an amino acid sequence that includes SEQ ID NO:27, SEQ IDNO:30, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:47, SEQ ID NO:50, SEQ IDNO:53, and SEQ ID NO:59, SEQ ID NO:102, SEQ ID NO:105, SEQ ID NO:108,SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:62, and/or SEQ ID NO:67.

[0096] As used herein, an isolated protein of the present invention canbe a full-length protein or any homolog of such a protein. An isolatedprotein of the present invention, including a homolog, can be identifiedin a straight-forward manner by the protein's ability to bind to areceptor or a protein. Examples of protein homologs of the presentinvention include proteins of the present invention in which amino acidshave been deleted (e.g., a truncated version of the protein, such as apeptide), inserted, inverted, substituted and/or derivatized (e.g., byglycosylation, phosphorylation, acetylation, myristoylation,prenylation, palmitoylation, amidation and/or addition ofglycerophosphatidyl inositol) such that the protein homolog includes atleast one epitope capable of eliciting an immune response against theparent protein, of binding to an antibody directed against the parentprotein and/or of binding to the parent's receptor, where the termparent refers to the longer and/or full-length protein that the homologis derived from. That is, when the homolog is administered to an animalas an immunogen, using techniques known to those skilled in the art, theanimal will produce an immune response against at least one epitope ofan immunoregulatory protein of the present invention, depending uponwhich protein is administered to an animal. The ability of a protein toeffect an immune response can be measured using techniques known tothose skilled in the art.

[0097] Homologs of proteins of the present invention can be the resultof natural allelic variation, including natural mutation. Proteinhomologs of the present invention can also be produced using techniquesknown in the art including, but not limited to, direct modifications tothe protein and/or modifications to the gene encoding the protein using,for example, classic or recombinant DNA techniques to effect random ortargeted mutagenesis.

[0098] One embodiment of the present invention is an IL-18 proteinselected from the group consisting of: (i) a protein having an aminoacid sequence selected from the group consisting of SEQ ID NO:2, SEQ IDNO:5, SEQ ID NO:8 and SEQ ID NO:12; and (ii) a protein encoded by anallelic variant of a nucleic acid molecule encoding a protein selectedfrom the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8 andSEQ ID NO:12. Another embodiment is a caspase-1 protein selected fromthe group consisting of: (i) a protein having an amino acid sequenceselected from the group consisting of SEQ ID NO:15, SEQ ID NO:18, SEQ IDNO:21, and SEQ ID NO:24; and (ii) a protein encoded by an allelicvariant of a nucleic acid molecule encoding a protein selected from thegroup consisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ IDNO:24. Yet another embodiment is a feline IL-12 single chain proteinselected from the group consisting of: (i) a protein having an aminoacid sequence selected from the group consisting of SEQ ID NO:38, andSEQ ID NO:44; and (ii) a protein encoded by an allelic variant of anucleic acid molecule encoding a protein selected from the groupconsisting of SEQ ID NO:38, and SEQ ID NO:44; or a canine Il-12 singlechain protein selected from the group consisting of: (i) a proteinhaving an amino acid sequence selected from the group consisting of SEQID NO:62 and SEQ ID NO:67; and (ii) a protein encoded by an allelicvariant of a nucleic acid molecule encoding a protein selected from thegroup consisting of SEQ ID NO:62 and SEQ ID NO:67.

[0099] One embodiment of the present invention includes an isolatedIL-18 protein selected from the group consisting of (i) an isolatedprotein of at least 25 amino acids in length, wherein said protein hasan at least 25 contiguous amino acid region identical in sequence to a25 contiguous amino acid region selected from the group consisting ofSEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ ID NO:12; and (ii) anisolated protein having an amino acid sequence that is at least 92percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ ID NO:12,and a fragment thereof of at least 30 nucleotides. Preferred proteinshave an at least 15 contiguous amino acid region identical with a 15contiguous amino acid region, an at least 20 contiguous amino acidregion identical with a 20 contiguous amino acid region, an at least 30contiguous amino acid region identical with a 30 contiguous amino acidregion, an at least 40 contiguous amino acid region identical with a 40contiguous amino acid region, an at least 50 contiguous amino acidregion contiguous with a 50 contiguous amino acid region, an at least 75contiguous amino acid region contiguous with a 75 contiguous amino acidregion, preferably an at least 100 contiguous amino acid regioncontiguous with a 100 contiguous amino acid region, and most preferablya full-length protein identical in sequence to a full-length protein ofan amino acid sequence selected from the group consisting of SEQ IDNO:2, SEQ ID NO:5, SEQ ID NO:8, and SEQ ID NO:12. In another embodiment,preferred proteins have an amino acid sequence that is at least 90percent identical, at least 92 percent identical, preferably at least 94percent identical, preferably at least 96 percent identical, and evenmore preferably at least about 98 percent identical to an amino acidsequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:5,SEQ ID NO:8, and SEQ ID NO:12, and a fragment thereof of at least 20amino acids, at least 30 amino acids, at least 50 amino acids, at least75 amino acids, preferably at least 100 amino acids, and more preferablya full-length protein.

[0100] In a preferred embodiment, IL-18 proteins of the presentinvention has a function selected from the group consisting of: (i)eliciting an immune response against an IL-18 protein having an aminoacid sequence selected from the group consisting of SEQ ID NO:2, SEQ IDNO:5, SEQ ID NO:8, and SEQ ID NO:12, (ii) selectively binding to anantibody raised against an IL-18 protein having an amino acid sequenceselected from the group consisting of SEQ ID NO:2, SEQ ID NO:5, SEQ IDNO:8, and SEQ ID NO:12, and (iii) exhibiting IL-18 activity.

[0101] One embodiment of the present invention includes an isolatedcaspase-1 protein selected from the group consisting of (i) an isolatedprotein of at least 25 amino acids in length, wherein said protein hasan at least 25 contiguous amino acid region identical in sequence to a25 contiguous amino acid region selected from the group consisting ofSEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24; and (ii) anisolated protein having an amino acid sequence that is at least 85percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ IDNO:24, and a fragment thereof of at least 30 nucleotides. Preferredproteins have an at least 25 contiguous amino acid region identical witha 25 contiguous amino acid region, an at least 20 contiguous amino acidregion identical with a 20 contiguous amino acid region, an at least 30contiguous amino acid region identical with a 30 contiguous amino acidregion, an at least 40 contiguous amino acid region identical with a 40contiguous amino acid region, an at least 50 contiguous amino acidregion contiguous with a 50 contiguous amino acid region, an at least 75contiguous amino acid region contiguous with a 75 contiguous amino acidregion, preferably an at least 100 contiguous amino acid regioncontiguous with a 100 contiguous amino acid region, and most preferablya full-length protein identical in sequence to a full-length protein ofan amino acid sequence selected from the group consisting of SEQ IDNO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ ID NO:24. In anotherembodiment, preferred proteins have an amino acid sequence that is atleast 85 percent identical, at least 88 percent identical, preferably atleast 90 percent identical, and more preferably at least about 95percent identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO:15, SEQ ID NO:18, SEQ ID NO:21, and SEQ IDNO:24, and a fragment thereof of at least 30 amino acids, at least 50amino acids, at least 75 amino acids, preferably at least 100 aminoacids, and more preferably a full-length protein.

[0102] In a preferred embodiment, a caspase protein of the presentinvention has a function selected from the group consisting of: (i)eliciting an immune response against a caspase-1 protein having an aminoacid sequence selected from the group consisting of SEQ ID NO:15, SEQ IDNO:18, SEQ ID NO:21, and SEQ ID NO:24, (ii) selectively binding to anantibody raised against a caspase-1 protein having an amino acidsequence selected from the group consisting of SEQ ID NO:15, SEQ IDNO:18, SEQ ID NO:21, and SEQ ID NO:24, and (iii) exhibiting caspase-1activity.

[0103] One embodiment of the present invention includes an isolatedIL-12 single chain protein comprising an IL-12 p40 subunit domain linkedto an IL-12 p35 subunit domain, wherein said p40 subunit domain isselected from the group consisting of (i) a p40 subunit protein havingan amino acid sequence that is at least 84 percent identical to an aminoacid sequence selected from the group consisting of SEQ ID NO:27 and SEQID NO:30, (ii) a p40 subunit protein comprising a fragment of a proteinof (i), wherein said fragment is at least 30 amino acids in length, and(iii) a p40 subunit protein comprising at least 23 contiguous aminoacids identical in sequence to at least 23 contiguous amino acids of anamino acid sequence selected from the group consisting of SEQ ID NO:27and SEQ ID NO:30. The p35 subunit is preferably selected from the groupconsisting of (i) a p35 subunit protein having an amino acid sequencethat is at least 84 percent identical to an amino acid sequence selectedfrom the group consisting of SEQ ID NO:33 and SEQ ID NO:36, (ii) a p35subunit protein comprising a fragment of a protein of (i), wherein saidfragment is at least 30 amino acids in length, and (iii) a p35 subunitprotein comprising at least 23 contiguous amino acids identical insequence to at least 23 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:33 and SEQ ID NO:36.Preferred amino acid sequences have an at least 23 contiguous amino acidregion identical with a 23 contiguous amino acid region, an at least 30contiguous amino acid region identical with a 30 contiguous amino acidregion, an at least 40 contiguous amino acid region identical with a 40contiguous amino acid region, an at least 50 contiguous amino acidregion contiguous with a 50 contiguous amino acid region, an at least 75contiguous amino acid region contiguous with a 75 contiguous amino acidregion, preferably an at least 100 contiguous amino acid regioncontiguous with a 100 contiguous amino acid region, and most preferablya full-length protein identical in sequence to a full-length protein ofan amino acid sequence selected from the group consisting of SEQ IDNO:27 and SEQ ID NO:30 In another embodiment, preferred proteins have anamino acid sequence that is at least 84 percent identical, at least 86percent identical, at least 88 percent identical, preferably at least 90percent identical, and more preferably at least about 95 percentidentical to an amino acid sequence selected from the group consistingof SEQ ID NO:27, SEQ ID NO:30, and a fragment thereof of at least 30amino acids, at least 50 amino acids, at least 75 amino acids,preferably at least 100 amino acids, and more preferably a full-lengthprotein.

[0104] In a preferred embodiment, an IL-12 single chain protein of thepresent invention has a function selected from the group consisting of:(i) eliciting an immune response against an IL-12 protein having anamino acid sequence selected from the group consisting of SEQ ID NO:27,SEQ ID NO:30, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:47, SEQ ID NO:50,SEQ ID NO:53, and SEQ ID NO:59, SEQ ID NO:102, SEQ ID NO:105, SEQ IDNO:108, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:62, and/or SEQ ID NO:67;(ii) selectively binding to an antibody raised against an IL-12 proteinhaving an amino acid sequence selected from the group consisting of SEQID NO:27, SEQ ID NO:30, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:47, SEQ IDNO:50, SEQ ID NO:53, and SEQ ID NO:59, SEQ ID NO:102, SEQ ID NO:105, SEQID NO:108, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:62, and/or SEQ IDNO:67; and (iii) exhibiting IL-12 activity.

[0105] One embodiment of the present invention includes an isolatedIL-12 single chain protein comprising an IL-12 p40 subunit domain linkedto an IL-12 p35 subunit domain, wherein said p40 subunit domain isselected from the group consisting of (i) a p40 subunit protein havingan amino acid sequence that is at least 84 percent identical to an aminoacid sequence selected from the group consisting of SEQ ID NO:53 and SEQID NO:59, (ii) a p40 subunit protein comprising a fragment of a proteinof (i), wherein said fragment is at least 40 amino acids in length, and(iii) a p40 subunit protein comprising at least 31 contiguous aminoacids identical in sequence to at least 31 contiguous amino acids of anamino acid sequence selected from the group consisting of SEQ ID NO:53and SEQ ID NO:59. The p35 subunit is preferably selected from the groupconsisting of (i) a p35 subunit protein having an amino acid sequencethat is at least 84 percent identical to an amino acid sequence selectedfrom the group consisting of SEQ ID NO:47 and SEQ ID NO:50, (ii) a p35subunit protein comprising a fragment of a protein of (i), wherein saidfragment is at least 40 amino acids in length, and (iii) a p35 subunitprotein comprising at least 31 contiguous amino acids identical insequence to at least 31 contiguous amino acids of an amino acid sequenceselected from the group consisting of SEQ ID NO:47 and SEQ ID NO:50.Preferred amino acid sequences have an at least 23 contiguous amino acidregion identical with a 23 contiguous amino acid region, an at least 30contiguous amino acid region identical with a 30 contiguous amino acidregion, an at least 40 contiguous amino acid region identical with a 40contiguous amino acid region, an at least 50 contiguous amino acidregion contiguous with a 50 contiguous amino acid region, an at least 75contiguous amino acid region contiguous with a 75 contiguous amino acidregion, preferably an at least 100 contiguous amino acid regioncontiguous with a 100 contiguous amino acid region, and most preferablya full-length protein identical in sequence to a full-length protein ofan amino acid sequence selected from the group consisting of SEQ IDNO:47, SEQ IID NO:50, SEQ ID NO:53, and SEQ ID NO:59. In anotherembodiment, preferred proteins have an amino acid sequence that is atleast 84 percent identical, at least 86 percent identical, at least 88percent identical, preferably at least 90 percent identical, and morepreferably at least about 95 percent identical to an amino acid sequenceselected from the group consisting of SEQ ID NO:47, SEQ ID NO:50, SEQ IDNO:53, and SEQ ID NO:59, and a fragment thereof of at least 30 aminoacids, at least 50 amino acids, at least 75 amino acids, preferably atleast 100 amino acids, and more preferably a full-length protein.

[0106] In a preferred embodiment, an IL-12 single chain protein of thepresent invention has a function selected from the group consisting of:(i) eliciting an immune response against an IL-12 protein having anamino acid sequence selected from the group consisting of SEQ ID NO:62and SEQ ID NO:67, (ii) selectively binding to an antibody raised againstan IL-12 protein having an amino acid sequence selected from the groupconsisting of SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, SEQ ID NO:36,SEQ ID NO:47, SEQ ID NO:50, SEQ ID NO:53, and SEQ ID NO:59, SEQ IDNO:102, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:39, SEQ ID NO:40, SEQ IDNO:62, and/or SEQ ID NO:67, and (iii) exhibiting IL-12 activity.

[0107] One embodiment of the present invention is a therapeuticcomposition that, when administered to a animal in an effective manner,is capable of protecting that animal from a disease such as, forexample, allergy, cancer or inflammation. Therapeutic compositions ofthe present invention include protective compounds that are capable ofregulating feline IL-18, feline caspase-1, or feline or canine IL-12protein amounts and/or activity. A protective compound of the presentinvention is capable of regulating feline IL-18, feline caspase-1, orfeline or canine IL-12 activity and/or availability. Examples ofprotective compounds related to feline and canine proteins of thepresent invention include an isolated antibody that selectively binds toeither feline IL-18, feline caspase-1, or feline or canine IL-12 orother inhibitors or activators of feline IL-18, feline caspase-1, orfeline or canine IL-12 activity or amount. Other examples of protectivecompounds include an isolated nucleic acid molecule of the presentinvention; an isolated protein of the present invention; a mimetope of aprotein of the present invention, a multimeric form of any of saidproteins, or an inhibitor identified by its ability to inhibit theactivity of any of said proteins; such an inhibitor can inhibit bindingof the respective protein with its receptor, or inhibit the activity ofthe respective protein. Methods to perform such assays to measurebinding and/or activity of protein of the present invention are known tothose of skill in the art, and are described, for example, in Janeway etal., ibid. As such, these protective compounds may include antibodies,peptides, substrate analogs, and other large or small molecules whichcan be organic or inorganic. As used herein, a protective compoundrefers to a compound, that when administered to an animal in aneffective manner, is able to treat, ameliorate, and/or prevent a diseasedue to allergy, cancer or infection. Examples of proteins, nucleic acidmolecules, antibodies and/or inhibitors of the present invention aredisclosed herein.

[0108] The present invention also includes a therapeutic compositioncomprising at least one compound of the present invention in combinationwith at least one additional therapeutic compound. Examples of suchcompounds are disclosed herein.

[0109] The efficacy of a therapeutic composition of the presentinvention to protect an animal from a disease mediated by feline IL-18,feline caspase-1, or feline or canine IL-12 can be tested in a varietyof ways including, but not limited to, detection of protectiveantibodies (using, for example, proteins or mimetopes of the presentinvention), detection of the amount of feline IL-18, feline caspase-1,or feline or canine IL-12, or detection of cellular immunity within thetreated animal. Therapeutic compositions can be tested in animal modelssuch as mice. Such techniques are known to those skilled in the art.

[0110] Therapeutic compounds of the present invention can beadministered to any animal susceptible to such therapy, preferably tomammals, and more preferably to dogs, cats, humans, ferrets, horses,cattle, sheep and/or other pets, economic food animals, and/or zooanimals. Preferred animals include dogs and cats.

[0111] A therapeutic composition of the present invention isadministered to an animal in an effective manner such that thecomposition is capable of regulating an immune response in that animal.Therapeutic compositions of the present invention can be administered toanimals prior to the onset of a disease (i.e. as a preventative vaccine)and/or can be administered to animals after onset of a disease in orderto treat the disease (i.e. as a therapeutic vaccine). Preferred diseasesto prevent and/or treat include autoimmune diseases, allergic reactions,infectious diseases, tumor development, inflammatory diseases and/orgraft rejection. In one embodiment, a therapeutic composition of thepresent invention is administered with an antigen to enhance an immuneresponse against that antigen. Such administration can include, but isnot limited to, oral, intravenous, intramuscular, intra ocular, mucosal,intranasal, subcutaneous, topical or transdermal application. In orderto protect an animal from disease, a therapeutic composition of thepresent invention is administered to the animal in an effective mannersuch that the composition is capable of protecting that animal from adisease. Therapeutic compositions of the present invention can beadministered to animals prior to disease in order to prevent diseaseand/or can be administered to animals after disease occurs. The exactdose, administration regimen, and administration route of therapeuticcompositions of the present invention can be determined by one skilledin the art. A suitable single dose is a dose that is capable ofregulating the immune response in an animal when administered one ormore times over a suitable time period. For example, a preferred singledose of a protein, mimetope or antibody therapeutic composition is fromabout 1 microgram (μg) to about 10 milligrams (mg) of the therapeuticcomposition per kilogram body weight of the animal. Booster vaccinationscan be administered from about 2 weeks to several years after theoriginal administration. Booster administrations preferably areadministered when the immune response of the animal becomes insufficientto protect the animal from disease. A preferred administration scheduleis one in which from about 10 μg to about 1 mg of the therapeuticcomposition per kg body weight of the animal is administered from aboutone to about two times over a time period of from about 2 weeks to about12 months.

[0112] A therapeutic composition of the present invention can include atleast one of the following: excipient, an adjuvant and a carrier.Therapeutic compositions of the present invention can be formulated inan excipient that the animal to be treated can tolerate. Examples ofsuch excipients include water, saline, Ringer's solution, dextrosesolution, Hank's solution, and other aqueous physiologically balancedsalt solutions. Nonaqueous vehicles, such as fixed oils, sesame oil,ethyl oleate, or triglycerides may also be used. Other usefulformulations include suspensions containing viscosity enhancing agents,such as sodium carboxymethylcellulose, sorbitol, or dextran. Excipientscan also contain minor amounts of additives, such as substances thatenhance isotonicity and chemical stability. Examples of buffers includephosphate buffer, bicarbonate buffer and Tris buffer, while examples ofpreservatives include thimerosal, or o-cresol, formalin and benzylalcohol. Standard formulations can either be liquid injectables orsolids which can be taken up in a suitable liquid as a suspension orsolution for injection. Thus, in a non-liquid formulation, the excipientcan comprise dextrose, human serum albumin, preservatives, etc., towhich sterile water or saline can be added prior to administration.

[0113] Therapeutic compositions of the present invention can include anadjuvant. Adjuvants are agents that are capable of enhancing the immuneresponse of an animal to a specific antigen. Suitable adjuvants include,but are not limited to, cytokines, chemokines, and compounds that inducethe production of cytokines and chemokines (e.g., granulocyte macrophagecolony stimulating factor (GM-CSF), granulocyte colony stimulatingfactor (G-CSF), macrophage colony stimulating factor (M-CSF), colonystimulating factor (CSF), erythropoietin (EPO), interleukin 2 (IL-2),interleukin-3 (IL-3), interleukin 4 (IL-4), interleukin 5 (IL-5),interleukin 6 (IL-6), interleukin 7 (IL-7), interleukin 8 (IL-8),interleukin 10 (IL-10), interferon gamma, transforming growth factorbeta, RANTES (regulated upon activation, normal T cell expressed andpresumably secreted), macrophage inflammatory proteins (e.g., MIP-1alpha and MIP-1 beta), and Leishmania elongation initiating factor(LEIF); bacterial components (e.g., endotoxins, in particularsuperantigens, exotoxins and cell wall components); aluminum-basedsalts; calcium-based salts; silica; polynucleotides; toxoids; serumproteins, viral coat proteins; block copolymer adjuvants (e.g., Hunter'sTitermax™ adjuvant (Vaxcel™, Inc. Norcross, Ga.), Ribi adjuvants (RibiImmunoChem Research, Inc., Hamilton, Mont.); and saponins and theirderivatives (e.g., Quil A (Superfos Biosector A/S, Denmark). Proteinadjuvants of the present invention can be delivered in the form of theprotein themselves or of nucleic acid molecules encoding such proteinsusing the methods described herein.

[0114] Therapeutic compositions of the present invention can include acarrier. Carriers include compounds that increase the half-life of aprotective compound in the treated animal. Suitable carriers include,but are not limited to, polymeric controlled release vehicles,biodegradable implants, liposomes, other lipid or lipid containingformulations, including cationic lipids or lipid mixtures includingcationic lipids, bacteria, viruses, other cells, oils, esters, andglycols.

[0115] A therapeutic composition can be a controlled release formulationthat is capable of slowly releasing a protective compound of the presentinvention into an animal. As used herein, a controlled releaseformulation comprises a composition or protective compound of thepresent invention in a controlled release vehicle. Suitable controlledrelease vehicles include, but are not limited to, biocompatiblepolymers, other polymeric matrices, capsules, microcapsules,microparticles, bolus preparations, osmotic pumps, diffusion devices,liposomes, lipospheres, other lipids or lipid-containing formulationsand transdermal delivery systems. Other controlled release formulationsof the present invention include liquids that, upon administration to ananimal, form a solid or a gel in situ. Preferred controlled releaseformulations are biodegradable, i.e., bioerodible.

[0116] A preferred controlled release formulation of the presentinvention is capable of releasing a composition of the present inventioninto the blood of the treated animal at a constant rate sufficient toattain therapeutic dose levels of the composition to regulate an immuneresponse in an animal. The therapeutic composition is preferablyreleased over a period of time ranging from about 1 to about 12 months.A controlled release formulation of the present invention is capable ofeffecting a treatment preferably for at least about 1 month, morepreferably for at least about 3 months, even more preferably for atleast about 6 months, even more preferably for at least about 9 months,and even more preferably for at least about 12 months.

[0117] According to one embodiment, a nucleic acid molecule of thepresent invention can be administered to an animal in a fashion toenable expression of that nucleic acid molecule into a therapeuticprotein or therapeutic RNA (e.g. antisense RNA, ribozyme, triple helixforms or RNA drug) in the animal. Nucleic acid molecules can bedelivered to an animal in a variety of methods including, but notlimited to, (a) administering a naked (i.e. not packaged in a viral coator cellular membrane) nucleic acid as a genetic vaccine (e.g. as nakedDNA or RNA molecules, such is taught, for example, in Wolff et al.,1990, Science 247, p 1465-68) or (b) administering a nucleic acidmolecule packaged as a recombinant virus vaccine or as a recombinantcell vaccine (i.e. the nucleic acid molecule is delivered by a viral orcellular vehicle).

[0118] One embodiment of a therapeutic composition of the presentinvention is a naked nucleic acid, a recombinant virus or a recombinantcell vaccine or therapy. Naked nucleic acid molecules of the presentinvention can be administered by a variety of methods. Suitable deliverymethods include, for example, intramuscular injection, subcutaneousinjection, intradermal injection, intradermal scarification, particlebombardment, oral application, topical application and nasalapplication, with intramuscular injection, intradermal injection,intradermal scarification and particle bombardment being preferred. Apreferred single dose of a naked nucleic acid molecule ranges from about1 nanogram (ng) to about 1 milligram (mg), depending on the route ofadministration and/or method of delivery, as can be determined by thoseskilled in the art. Examples of administration methods are disclosed,for example, in U.S. Pat. No. 5,204,253, by Bruner, et al., issued Apr.20, 1993, PCT Publication No. WO 95/19799, published Jul. 27, 1995, byMcCabe, and PCT Publication No. WO 95/05853, published Mar. 2, 1995, byCarson, et al. Naked nucleic acid molecules of the present invention canbe contained in an aqueous excipient (e.g., phosphate buffered saline)and/or with a carrier (e.g., lipid-based vehicles), or it can be boundto microparticles (e.g., gold particles).

[0119] According to one embodiment, a nucleic acid molecule of thepresent invention can be administered to an animal in a fashion toenable expression of that nucleic acid molecule into a protectiveprotein or protective RNA, e.g., antisense RNA, ribozyme, triple helixform or RNA drug, in the animal. Nucleic acid molecules can be deliveredto an animal in a variety of methods including, but not limited to, (a)administering a naked, i.e., not packaged in a viral coat or cellularmembrane, nucleic acid as a genetic therapy or vaccine, e.g., as nakedDNA or RNA molecules, such as is taught, for example in Wolff et al.,1990, Science 247, 1465-1468, or (b) administering a nucleic acidmolecule packaged as a recombinant virus therapy or vaccine or as arecombinant cell therapy or vaccine, i.e., the nucleic acid molecule isdelivered by a viral or cellular vehicle.

[0120] A genetic, i.e., naked nucleic acid, therapy vaccine of thepresent invention includes a nucleic acid molecule of the presentinvention and preferably includes a recombinant molecule of the presentinvention that preferably is replication or otherwise amplification,competent. A genetic therapy or vaccine of the present invention cancomprise one or more nucleic acid molecules of the present inventionoperatively linked to a transcriptional control sequence in the form of,for example, a dicistronic recombinant molecule. Preferred viral vectorsinclude those based on alphaviruses, poxviruses, adenoviruses,herpesviruses, picornaviruses, and/or retroviruses, with those based onalphaviruses (such as sindbis or Semliki forest virus) species-specificherpesviruses and/or poxviruses being particularly preferred. Anysuitable transcription control sequence can be used, including thosedisclosed as suitable for protein production. Particularly preferredtranscription control sequences include cytomegalovirus immediate early(preferably in conjunction with Intron-A), Rous sarcoma virus longterminal repeat, and tissue-specific transcription control sequences, aswell as transcription control sequences endogenous to viral vectors ifviral vectors are used. The incorporation of a “strong” polyadenylationsignal is also preferred.

[0121] Genetic therapies and vaccines of the present invention can beadministered in a variety of ways, with intramuscular, subcutaneous,intradermal, transdermal, intranasal, topical and oral routes ofadministration being preferred. A preferred single dose of a genetictherapy or vaccine ranges from about 1 nanogram (ng) to about 600 μg,depending on the route of administration and/or method of delivery, ascan be determined by those skilled in the art. Suitable delivery methodsinclude, for example, by injection, as drops, aerosolized and/ortopically. Genetic therapies or vaccines of the present invention can becontained in an aqueous excipient, e.g., phosphate buffered saline,alone or in a carrier, e.g., lipid-based vehicles. One embodiment is anucleic acid-lipid complex, preferably a nucleic acid-cationic lipidcomplex.

[0122] A recombinant virus therapy or vaccine of the present inventionincludes a recombinant molecule of the present invention that ispackaged in a viral coat and that can be expressed in an animal afteradministration. Preferably, the recombinant molecule is packaging- orreplication-deficient and/or encodes an attenuated virus. A number ofrecombinant viruses can be used, including, but not limited to, thosebased on alphaviruses, poxviruses, adenoviruses, herpesviruses,picornaviruses, and retroviruses. Preferred recombinant virus vaccinesare those based on alphaviruses, such as Sindbis virus, raccoonpoxviruses, species-specific herpesviruses and species-specificpoxviruses. An example of methods to produce and use recombinant virustherapies and vaccines is disclosed in U.S. Pat. No. 5,766,602, Xiong etal., issued Jun. 16, 1998; U.S. Pat. No. 5,753,235, Haanes et al.,issued May 19, 1998; and U.S. Pat. No. 5,804,197, Haanes et al., issuedSep. 8, 1998, all of which are incorporated by reference herein in theirentireties.

[0123] When administered to an animal, a recombinant virus therapy orvaccine of the present invention infects cells within the immunizedanimal and directs the production of a protective protein or RNA nucleicacid molecule that is capable of protecting the animal from a disease.For example, a recombinant virus vaccine comprising a feline IL-18nucleic acid molecule of the present invention can be administeredaccording to a protocol that results in the animal producing asufficient immune response to protect itself from a disease mediated byIL-18. In another embodiment of the present invention a feline IL-18nucleic acid molecule can be used as therapy to treat a disease. Arecombinant virus vaccine comprising a feline IL-18 nucleic acidmolecule can be administered to an animal with clinical signs of diseaseaccording to a protocol that results in reduction and/or termination ofclinical signs of disease. A preferred single dose of a recombinantvirus therapy or vaccine of the present invention is from about 1×10⁴ toabout 1×10⁸ virus plaque forming units (pfu) per kilogram body weight ofthe animal. Administration protocols are similar to those describedherein for protein-based vaccines, with subcutaneous, intramuscular,intranasal, topical and oral administration routes being preferred.

[0124] A recombinant cell therapy or vaccine of the present inventionincludes recombinant cells of the present invention that express atleast one protein of the present invention. Preferred recombinant cellsfor this embodiment include Salmonella, E. coli, Listeria,Mycobacterium, S. frugiperda, yeast, (including Saccharomyces cerevisiaeand Pichia pastoris), BHK, CV-1, myoblast G8, COS, e.g.,COS-7, Vero,MDCK and CRFK recombinant cells. Recombinant cell therapy or vaccines ofthe present invention can be administered in a variety of ways but havethe advantage that they can be administered orally, preferably at dosesranging from about 10⁸ to about 10¹² cells per kilogram body weight.Administration protocols are similar to those described herein forprotein-based vaccines. Recombinant cell vaccines can comprise wholecells, cells stripped of cell walls or cell lysates.

[0125] In one embodiment of the present invention, a method to regulatean immune response in an animal by administering the therapeuticcompound to an animal preferably a canine or feline, wherein thecomposition comprises a component selected from the group consisting ofan excipient, an adjuvant and a carrier.

[0126] Proteins of the present invention can be used to developregulatory compounds including inhibitors and activators that, whenadministered to an animal in an effective manner, are capable ofprotecting that animal from disease mediated by IL-18, caspase-1 orIL-12. Preferred regulatory compounds derived from the present inventioninclude inhibitors and activators. In accordance with the presentinvention, the ability of a regulatory compound, including an inhibitoror activator, of the present invention to protect a felid or canid fromdisease mediated by IL-18, caspase-1 or IL-12 refers to the ability ofthat compound to, for example, treat, ameliorate or prevent a diseasemediated by IL-18, caspase-1 or IL-12 in that animal.

[0127] An IL-18, caspase-1 or IL-12 single chain inhibitor of thepresent invention is identified by its ability to bind to, modify, orotherwise interact with, an IL-18, caspase-1 or IL-12 single chainprotein of the present invention, thereby inhibiting the activity of theprotein. Suitable inhibitors of activity are compounds that inhibit theactivity of the proteins of the present invention in at least one of avariety of ways: (1) by binding to or otherwise interacting with orotherwise modifying the protein binding, (2) by interacting with otherregions of the protein to inhibit activity, for example, by allostericinteraction, and (3) by binding to or otherwise interacting with orotherwise modifying a protein receptor binding site such that theprotein is less likely to bind to the protein receptor binding site.Inhibitors of IL-18, caspase-1 and IL-12 single chain proteins arepreferably relatively small compounds.

[0128] An embodiment of the present invention includes use of one of thefollowing methods to identify a compound capable of regulating an immuneresponse in an animal: (a) contacting an isolated feline IL-18 proteinwith a putative inhibitory compound under conditions in which, in theabsence of the compound, the protein has T cell stimulating activity;and determining if the putative inhibitory compound inhibits theactivity; (b) contacting an isolated feline caspase-1 protein with aputative inhibitory compound under conditions in which, in the absenceof the compound, the protein cleaves precursor IL-18 resulting in abiologically active mature IL-18; and determining if the putativeinhibitory compound inhibits the activity; and (c) contacting anisolated IL-12 single chain protein with a putative inhibitory compoundunder conditions in which, in the absence of the compound, the proteinhas T cell proliferation stimulating activity; and determining if theputative inhibitory compound inhibits the activity.

[0129] A variety of methods are known to one skilled in the art todetect binding of an IL-18, caspase-1 or IL-12 protein to its bindingpartner (e.g., an antibody or receptor, as appropriate). Such methodscan be used to detect IL-12, casp-1, or IL-18, or Abs or other bindingpartners thereof in a biological sample or to produce inhibitors of suchinteractions. Such methods include, but are not limited to an assay inwhich, for example, IL-18 and an IL-18 binding partner can interactand/or bind to each other, using, for example, the yeast two-hybridsystem, see for example, Luban, et al. 1995, Curr. Opin. Biotechnol., 6,59-64; and identifying those proteins that specifically bind to theIL-18 protein binding domain. Additional methods to identifyprotein-protein interactions include Biacore® screening, confocalimmunofluorescent microscopy, UV cross-linking, andimmunoprecipitations. An example of a protein binding domain is anIL-18-binding domain, and a protein that would bind to an IL-18-bindingdomain would be IL-18. Additional teachings of general characteristicsof reagents for use in the detection of binding between two moieties(e.g., between IL-18 and its receptor) as well as methods to produce anduse such reagents are disclosed, for example, in United States Pat. No.5,958,880, issued Sep. 28, 1999, by Frank et al.; and PCT InternationalPublication No. WO 99/54349, published Oct. 28, 1999, by McCall et al.;each of these references is incorporated by reference herein in itsentirety; furthermore, the disclosed reagents and methods areincorporated by reference herein in their entireties. It is to be notedthat although the reagents and methods disclosed in each of thecitations do not relate to the proteins, nucleic acid molecules,antibodies and inhibitors of the present invention per se, the disclosedreagents and methods are applicable by those skilled in the art toreagents, kits and detection methods of the present invention.Furthermore, proteins of the present invention can be used to developregulatory compounds including inhibitors and activators that, whenadministered to a canid or felid in an effective manner are capable ofprotecting and treating that felid or canid from disease mediated byIL-18, caspase-1 or IL-12.

[0130] The following examples are provided for the purposes ofillustration and are not intended to limit the scope of the presentinvention. The following examples include a number of recombinant DNAand protein chemistry techniques known to those skilled in the art; see,for example, Sambrook et al., ibid.

EXAMPLE 1

[0131] Identification of the nucleic acid molecules of the feline IL-18is unexpected because initial attempts to isolate feline IL-18 nucleicacid molecules using standard cDNA screening techniques wereunsuccessful.

[0132] This example describes the isolation, sequencing and expressionof nucleic acid molecules encoding feline IL-118 proteins of the presentinvention.

[0133] A. Feline IL-18 nucleic acid molecules were isolated as follows:A cDNA mitogen library was prepared from cat peripheral bloodlymphocytes stimulated with ConA for 4 hours as previously described inExample 2 of PCT Publication No. WO 99/61618, entitled “Canine andFeline Immunoregulatory Proteins, Nucleic Acid Molecules, and UsesThereof,” inventors Gek-Kee Sim, Shumin Yang, Matthew Dreitz, and RamaniWonderling, filed May 28, 1999, which is incorporated by referenceherein in its entirety. An aliquot of this library was used as atemplate to isolate a feline IL-18 nucleic acid molecule by polymerasechain reaction (PCR). PCR amplification was performed using Amplitaq DNApolymerase™ (available from PE Applied Biosystems Inc, Foster City,Calif.). Two overlapping nucleic acid molecules encoding partial lengthfeline IL-18 proteins were obtained by using IL-18 specific primers incombination with cDNA library vector specific primers. All primers camefrom Life Technologies, Gaithersburg, Md. The sequence of the vectorforward primer (T3 primer) was 5′ GCCAAGCTCG AAATTAACCC TCACTAAAGG 3′(SEQ ID NO:72), and that of the vector reverse primer (T7 primer) was 5CGACGGCCAG TGAATTGTAA TACGACTC 3′ (SEQ ID NO:73). The sequence of theIL-18-specific forward primer (IL-18 Forward 85) was 5′ AGTGATGAAGGCCTGGAATC AGATTACTTT G 3′ (SEQ ID NO:74) and the sequence of theIL-18-specific reverse primer (L-18 Reverse 435) was 5′ ATGGCCTGGAACACTTCTCT GAAAGAATAT GA 3′ (SEQ ID NO:75). The first PCR amplificationwas done using T3 primer and IL-18 Reverse 435 primer and the second PCRamplification was done using IL-18 Forward 85 primer and T7 primer. ThePCR profile for both reactions were as follows: one initial denaturationstep at 94° C. for 5 minutes; then 43 cycles of the following: 94° C.for 30 seconds, then 59° C. for 30 seconds, then 72° C. for 2 minutes;followed by a final extension at 72° C. for 7 minutes. The PCR productsfrom both reactions were cloned into the TA-Cloning vector (availablefrom Invitrogen, San Diego, Calif.) and the nucleic acid molecules weresequenced using an ABI Prism™ Model 377 Automatic DNA Sequencer(available from PE Applied Biosystems Inc.). DNA sequencing reactionswere performed using Prism™ dRhodamine Terminator Cycle Sequencing ReadyReaction kits (available from PE Applied Biosystems Inc.). The PCRproduct from the first PCR amplification was sequenced and found tocontain 514 nucleotides and was denoted herein as nFeIL-18₅₁₄ (5′-endpartial clone) with a coding strand of SEQ ID NO:1, and a complementarystrand of SEQ ID NO:3. The PCR product from the second PCR amplificationwas sequenced and found to contain 502 nucleotides and was denotedherein as nFeIL-18₅₀₂ (3′-end partial clone) with a coding strand of SEQID NO:4, and a complementary strand of SEQ ID NO:6. These two nucleicacid molecules shared more than 280 base pairs (bp) and togetherprovided the sequence for the complete feline IL-18 open reading frame.Translation of SEQ ID NO:1 suggests that nucleic acid moleculenFeIL-18-N₅₁₄ encodes an N-terminal portion of PFeIL-18-N protein, ofabout 133 amino acids, denoted herein as PFe IL-18-N₁₃₃, the amino acidsequence of which is presented in SEQ ID NO:2, assuming an open readingframe having an initiation codon spanning from nucleotide 114 throughnucleotide 116 of SEQ ID NO:1 and a stop codon spanning from nucleotide510 through nucleotide 512 of SEQ ID NO:1. Translation of SEQ ID NO:4suggests that nucleic acid molecule nFeIL-18-C₅₀₂ encodes an C-terminalportion of PFeIL-18-C protein, of about 154 amino acids, denoted hereinas PFe IL-18-C₁₅₄, the amino acid sequence of which is presented in SEQID NO:5, assuming an open reading frame having an initiation codonspanning from nucleotide 3 through nucleotide 5 of SEQ ID NO:4 and astop codon spanning from nucleotide 462 through nucleotide 464 of SEQ IDNO:4.

[0134] Based on the sequence data obtained from these two nucleic acidmolecules two new primers were made to isolate a cDNA encodingfull-length feline IL-18. The IL-18 Full Forward primer sequence was 5′AACTATTGAG CACAGGGATA AAGATGACTG 3′ (SEQ ID NO:76) and IL-18 FullReverse primer sequence was 5′ AATATCTAAT TCTTGTTTTG AACAGTGAAC ATT 3′(SEQ ID NO:77). The PCR amplification was performed using these twoprimers and Amplitaq DNA polymerase™ (available from PE AppliedBiosystems Inc.) and an aliquot of the cDNA library prepared from catperipheral blood lymphocytes stimulated with ConA for 4 hours. The PCRprofile was as follows: one initial denaturation step at 94° C. for 5minutes; then 43 cycles of the following: 94° C. for 30 seconds, then53° C. for 30 seconds, then 72° C. for 90 seconds; followed by a finalextension at 72° C. for 7 minutes. The PCR product was cloned into theTA-Cloning vector (available from Invitrogen, San Diego, Calif.) and thenucleic acid molecule insert was sequenced using an ABI PRISM™ Model 377Automatic DNA Sequencer (available from PE Applied Biosystems Inc.). DNAsequencing reactions were performed using PRISM™ dRhodamine TerminatorCycle Sequencing Ready Reaction kits (available from PE AppliedBiosystems Inc.). This PCR product the FeIL-18 containing region ofwhich is denoted nFeIL-18₆₀₇ was found to encode a full-length FeIL-18protein. The nucleotide sequence of the coding strand of nFeIL-18₆₀₇ isrepresented herein as SEQ ID NO:7, and its complement is denoted by SEQID NO:10. Translation of the open reading frame in SEQ ID NO:7, denotedherein as nFeIL 18₅₇₆, the coding strand of which is denoted SEQ IDNO:9, and the complementary strand denoted SEQ ID NO:41 suggests thatfeline IL-18 encodes a protein containing 192 amino acids, referred toherein as PFeIL-18₁₉₂, with a SEQ ID NO:8. The nucleic acid sequenceencoding feline IL-18 protein assumes an open reading frame in which thefirst codon spans from nucleotide 24 through 26 of SEQ ID NO:7, and thelast codon spans from nucleotide 597 through nucleotide 599 of SEQ IDNO:7. The encoded protein has a predicted molecular weight of about 21.3kiloDaltons (kDa) for the precursor protein. The IL-18 precursor proteindoes not contain a signal sequence; in order for IL-18 to bebiologically active the precursor is cleaved by caspase-1. The putativecaspase-1 cleavage site is between amino acid positions 35 and 36 of thefeline IL-18 precursor protein. Nucleic acid molecule nFeIL-18₄₇₁, whichencodes the mature protein contains a coding strand with SEQ ID NO:11,and a complementary strand with SEQ ID NO:13. The amino acid sequence ofthe mature protein, denoted herein as PFeIL-18₁₅₇ is SEQ ID NO:12 andthe mature protein has a predicted molecular weight of about 17.4 kDa.Sequence analysis was performed using DNAsis™, available from HitachiSoftware, San Bruno, Calif. using the alignment settings of: gap penaltyset at 5, k-tuple set at 3, number of top diagonals set at 5, windowsize set at 5, fixed gap penalty set at 10 and floating gap penalty setat 10.

[0135] B. In an attempt to express a mature feline IL-18 protein in amammalian cell line, the region encoding only the mature IL-18 protein(SEQ ID NO:11) was isolated from the feline cDNA library described inExample 1A using the following primers: IL-18 MatNgo Forward primerwhich has the sequence 5′ TATGCCGGCT ACTTTGGCAA GCTTGAACAT AAACTC 3′(SEQ ID NO:78) and IL-18 MatXho Reverse primer which has the sequence 5′GGCCTCGAGC TAATTCTTGT TTTGAACAGT GAACATT 3′ (SEQ ID NO:79). The PCRamplification was performed using these two primers and Amplitaq DNApolymerase™ (available from PE Applied Biosystems Inc.) and an aliquotof the cDNA library prepared from cat peripheral blood lymphocytesstimulated with ConA for 4 hours. The PCR profile was as follows: oneinitial denaturation step at 94° C. for 5 minutes; then 43 cycles of thefollowing: 94° C. for 30 seconds, then 53° C. for 30 seconds, then 72°C. for 90 seconds; followed by a final extension at 72° C. for 7minutes. The PCR products were digested with Ngo MI and Xho Irestriction enzymes (available from New England Biolabs, Beverly, Mass.)and ligated downstream of nucleotides encoding a tissue plasminogenactivator (tPA) signal sequence contained in the CMV-IntronA-tPA vector(available from Invitrogen). The construct was sequenced using an ABIPrism™ Model 377 Automatic DNA Sequencer (available from PE AppliedBiosystems Inc.). DNA sequencing reactions were performed using Prism™dRhodamine Terminator Cycle Sequencing Ready Reaction kits (availablefrom PE Applied Biosystems Inc.). This construct encoded the maturefeline IL-18 protein with the tPA signal sequence. When Chinese hamsterovary (CHO) cells (available from ATCC, Rockville, Md.) were transientlytransfected with this construct, using techniques known to those skilledin the art and cell pellets and supernatants were harvested after 48hrs. Western analysis was performed on the cell pellets and supernatantsamples using a polyclonal antibody against human IL-18 (available fromBiosource International, Camarillo, Calif.). A faint band of theexpected size (about 17.4 kDa) was detected in the cell pellet and notin the supernatant, indicating that IL-18 is produced by this constructbut it is not exported out of the cell at detectable levels. While notbeing bound by theory, it is believed that caspase-1 plays a key role inthe processing of native IL-18 precursor in cells where IL-18 isproduced, co-expression of full-length feline IL-18 along with thefeline caspase-1 may be necessary for the proper processing of the IL-18precursor and enhanced secretion of the processed IL-18 maturepolypeptide.

EXAMPLE 2

[0136] This example describes the isolation and sequencing of nucleicacid molecules encoding feline caspase-1 proteins of the presentinvention.

[0137] Feline caspase-1 nucleic acid molecules were isolated as follows:A cDNA mitogen library was prepared from cat peripheral bloodlymphocytes stimulated with ConA for 4 hours as described in Example 1.An aliquot of this library was used as a template to isolate a felinecaspase-1 by polymerase chain reaction (PCR). PCR amplification wasperformed using Amplitaq DNA polymerase™ (available from PE AppliedBiosystems Inc.). The forward and reverse primers were designed based onhuman caspase-1 sequences. The forward primer (Casp-1For) had a sequenceof 5′ ATGGCCGACA AGGTCCTGAA GGAGAAGA 3′ (SEQ ID NO:80) and the reverseprimer (Casp-1 Rev) had a sequence of 5′ TTAATGTCCT GGGAAGAGGTAGAAACATCT TGT 3′ (SEQ ID NO:81). The PCR profile was as follows: oneinitial denaturation step at 94° C. for 5 minutes; then 43 cycles of thefollowing: 94° C. for 45 seconds, then 53° C. for 45 seconds, then 72°C. for 2 minutes; followed by a final extension at 72° C. for 7 minutes.The PCR product was cloned into the TA-Cloning vector (available fromInvitrogen, San Diego, Calif.) and sequenced using an ABI Prism™ Model377 Automatic DNA Sequencer (available from PE Applied Biosystems Inc.).DNA sequencing reactions were performed using Prism™ dRhodamineTerminator Cycle Sequencing Ready Reaction kits (available from PEApplied Biosystems Inc.). The PCR product was found to contain thecomplete full-length feline caspase-1 except for the primer region whichwas based on the human caspase-1 sequence. The nucleotide sequence ofthe coding strand of this PCR product is represented herein asnFeCasp-1₁₂₃₃ with a SEQ ID NO:14, and its complement is denoted by SEQID NO:16. Translation of SEQ ID NO:14 suggests that nucleic acidmolecule nFeCasp-1₁₂₃₃ encodes a full-length nFeCasp-1₁₂₃₃ protein, ofabout 410 amino acids, denoted herein as PFeCasp-1₄₁₀, the amino acidsequence of which is presented in SEQ ID NO:15, assuming an open readingframe having an initiation codon spanning from nucleotide 1 throughnucleotide 3 of SEQ ID NO:14 and a stop codon spanning from nucleotide408 through nucleotide 410 of SEQ ID NO:14.

[0138] Additional primers were made based on the feline caspase-1sequence of nFeCasp-1₁₂₃₃ in order to obtain two nucleic acid moleculesspanning the 5′ and 3′ end of the feline caspase-1 open reading frame.Two feline caspase-1 nucleic acid molecules were generated using felinecaspase-1 specific primers in combination with cDNA library vectorspecific primers. The sequence of the vector forward primer (T3 primer)was 5′ GCCAAGCTCG AAATTAACCC TCACTAAAGG 3′ (SEQ ID NO:72), and that ofthe vector reverse primer (T7 primer) was 5′ CGACGGCCAG TGAATTGTAATACGACTC 3′ (SEQ ID NO:73). The sequence of the felinecaspase-1-specific forward primer (Casp 271 Forward) was 5′ TCAAGCCCACAATCTGGAAA TTCTCA 3′(SEQ ID NO:82) and the sequence of the felinecaspase-1-specific reverse primer (Casp 895 Reverse) was 5′ CTGGAGAGTCACTGATCAAC AGTTCC 3′(SEQ ID NO:83). The first PCR amplification was doneusing T3 primer and Casp 895 Reverse primer and the second PCRamplification was done using Casp 271 Forward primer and T7 primer. ThePCR profile for both reactions was as follows: one initial denaturationstep at 94° C. for 5 minutes; then 43 cycles of the following: 94° C.for 45 seconds, then 52° C. for 45 seconds, then 72° C. for 2 minutes;followed by a final extension at 72° C. for 7 minutes. The PCR productsfrom both reactions that were greater than or equal to 1 kb were gelpurified and cloned into the TA-Cloning vector (available fromInvitrogen) and the nucleic acid molecules were sequenced using an ABIPrism™ Model 377 Automatic DNA Sequencer (available from PE AppliedBiosystems Inc.). DNA sequencing reactions were performed using Prism™dRhodamine Terminator Cycle Sequencing Ready Reaction kits (availablefrom PE Applied Biosystems Inc.). The nucleic acid molecules obtainedfrom these two PCR products represented two nucleic acid molecules offeline caspase-1. The region of the first PCR amplification wassequenced and found to contain 527 nucleotides denoted herein asnFeCasp-1-N₅₂₇ (5′-end partial clone) with a coding strand of SEQ IDNO:17, and a complementary strand of SEQ ID NO:19. The region of thesecond PCR amplification was sequenced and found to contain 500nucleotides denoted here as nFeCasp-1-C₅₀₀ (3′-end partial clone) with acoding strand of SEQ ID NO:20, and a complementary strand of SEQ IDNO:22. Translation of SEQ ID NO:17 suggests that nucleic acid moleculenFeCasp-1-N₅₂₆ encodes an N-terminal portion of PFeCasp-1-N protein, ofabout 169 amino acids, denoted herein as PFeCasp-1-N₁₆₉, the amino acidsequence of which is presented in SEQ ID NO:18, assuming an open readingframe having an initiation codon spanning from nucleotide 18 throughnucleotide 20 of SEQ ID NO:17 and a stop codon spanning from nucleotide522 through nucleotide 524 of SEQ ID NO:17. Translation of SEQ ID NO:20suggests that nucleic acid molecule nFeCasp-1-C₅₀₀ encodes an C-terminalportion of PFeCasp-1-C protein, of about 120 amino acids, denoted hereinas PFeCasp-1-C₁₂₀, the amino acid sequence of which is presented in SEQID NO:21, assuming an open reading frame having an initiation codonspanning from nucleotide 3 through nucleotide 5 of SEQ ID NO:20 and astop codon spanning from nucleotide 360 through nucleotide 362 of SEQ IDNO:20

[0139] Based on the sequence data obtained from nucleic acid moleculesnFeCasp-1-N₅₂₇ and nFeCasp-1-C₅₀₀, two new primers were made to isolatea cDNA encoding full-length feline caspase-1. The feline caspase-1full-length forward primer (CaspBamKozFor) sequence was 5′ ACAAGGATCCACCATGGCCG ACAAGGATCT GAAGGG 3′ (SEQ ID NO:84) and feline caspase-1full-length reverse primer (CaspXbaRev) sequence was 5′ CGCCTCTAGACCTCAATTGC CAGGGAAGAG ATAGAAGTA 3′ (SEQ ID NO:85). The PCR amplificationwas performed using these two primers and Amplitaq DNA polymerase™(available from PE Applied Biosystems Inc.) and an aliquot of the cDNAmitogen library prepared from cat peripheral blood lymphocytesstimulated with ConA for 4 hours. The PCR profile was as follows: oneinitial denaturation step at 94° C. for 5 minutes; then 43 cycles of thefollowing: 94° C. for 45 seconds, then 52° C. for 45 seconds, then 72°C. for 2 minutes; followed by a final extension at 72° C. for 7 minutes.The PCR product was cloned into the TA-Cloning vector (available fromInvitrogen) and the nucleic acid molecule inserts were sequenced usingan ABI Prism™ Model 377 Automatic DNA Sequencer (available from PEApplied Biosystems Inc.). DNA sequencing reactions were performed usingPrism™ dRhodamine Terminator Cycle Sequencing Ready Reaction kits(available from PE Applied Biosystems Inc.). This PCR product theFeCaspase-1 containing region of which is denoted nFeCasp-1₁₂₃₀ wasfound to encode the a full-length feline caspase-1 protein. Thenucleotide sequence of the coding strand of nFeCasp-1₁₂₃₀ is representedherein as SEQ ID NO 23, and its complement is denoted by SEQ ID NO:25.Translation of the open reading frame in SEQ ID NO:23, denoted here asnFeCasp-1₁₂₃₀, the coding strand of which is denoted SEQ ID NO:25suggests that feline caspase-1 encodes a protein containing 410 aminoacids, referred to herein as PFeCasp-1₄₁₀, with a SEQ ID NO:24. Thenucleic acid sequence encoding the protein assumes an open reading framein which the first codon spans from nucleotide 1 through 3 of SEQ IDNO:23, and the last codon spans from nucleotide 1228 nucleotide 1230 ofSEQ ID NO:23. The encoded protein has a predicted molecular weight ofabout 45.5 kDa. The feline caspase-1 protein is 9 amino acids longerthan mouse and rat caspase-1 proteins, 6 amino acids longer than dog andhuman caspase-1 proteins, and 5 amino acids longer than horse caspase-1proteins. Sequence analysis was performed using DNAsis™, available fromHitachi Software, San Bruno, Calif. using the alignment settings of: gappenalty set at 5, k-tuple set at 3, number of top diagonals set at 5,window size set at 5, fixed gap penalty set at 10 and floating gappenalty set at 10.

EXAMPLE 3

[0140] This example describes the isolation and sequencing of nucleicacid molecules encoding feline IL-12 single chain proteins of thepresent invention.

[0141] A. A pBluescript-Linker plasmid was constructed as follows: Twocomplementary oligonucleotides, 60 nucleotides in length weresynthesized. The oligonucleotides were allowed to hybridize to eachother in solution producing a double stranded DNA fragment that wouldserve as a linker between the cDNAs encoding the p40 and p35 subunits offeline IL-12. The sequence of the sense linker was 5′ CTGCAGTGGTGGCGGTGGCG GCGGATCTAG AAACTTGCCA ACCCCTACTC CATCCCCGGG 3′ (SEQ ID NO:83)and the sequence of the antisense linker was 5′ CCCGGGGATG GAGTAGGGGTTGGCAAGTTT CTAGATCCGC CGCCACCGCC ACCACTGCAG 3′ (SEQ ID NO:84). Equimolaramounts of sense linker and antisense linker were mixed and heated to95° C. for 10 minutes in a heat block. The heat block containing thesamples was removed from the heat source and allowed to cool to roomtemperature slowly, over a period of 4 hours. Then the hybridizedoligonucleotides were digested with PstI and SmaI restriction enzymes(available from New England Biolabs, Beverly, Mass.) and ligated intopBluescript SK⁺ vector (available from Stratagene, La Jolla, Calif.)digested with the same restriction enzymes to produce pBluescript-Linkerplasmid. The presence of the linker in the ligated pBluescript-Linkerplasmid was confirmed by sequencing conducted as described in Example 1.The pBluescript-Linker plasmid contained DNA coding for the followingelements: (1) the last two C-terminal amino acid residues of the p40subunit (i.e. C,S); (2) the seven amino acid residues of the linker(i.e. GGGGGGS); and (3) the first ten N-terminal amino acid residues ofthe mature p35 subunit mature protein (i.e. RNLPTPTPSP).

[0142] B. Feline IL-12 p40 nucleic acid molecule subunit was isolated asfollows: A cDNA mitogen library was prepared from cat peripheral bloodlymphocytes stimulated with ConA for 4 hours as previously described inExample 1. An aliquot of this library was used as a template to isolatea feline IL-12 p40 nucleic acid molecule subunit by polymerase chainreaction (PCR). The PCR amplification was performed using Amplitaq DNApolymerase™ (available from PE Applied Biosystems Inc.). The sequence ofthe forward primer was 5′ ATGCATCCTC AGCAGTTGGT CATCGCCT 3′ (SEQ IDNO:85), and that of the reverse primer was 5′ TGCAGGACAC GGATGCCCAGTTGCT3′ (SEQ ID NO:86). The PCR profile was as follows: one initialdenaturation step at 94° C. for 5 minutes; then 43 cycles of thefollowing: 94° C. for 45 seconds, then 50° C. for 45 seconds, then 72°C. for 2 minutes; followed by a final extension at 72° C. for 7 minutes.PCR products were cloned into the TA-Cloning vector (available fromInvitrogen) and the nucleic acid molecule inserts were sequenced asdescribed in Example 1. One of the sequenced PCR products contained 985nucleotides and was denoted herein as nFeIL-12 p40-N₉₈₅ with a codingstrand of SEQ ID NO:55, and a complementary strand of SEQ ID NO:57.Translation of SEQ ID NO:55 suggests that nucleic acid moleculenFeIL-12p40-N₉₈₅ encodes an N-terminal portion of PFeIL-12p40-N protein,of about 328 amino acids, denoted herein as PFe IL-12p40-N₃₂₈, the aminoacid sequence of which is presented in SEQ ID NO:56, assuming an openreading frame having an initiation codon spanning from nucleotide 1through nucleotide 3 of SEQ ID NO:55 and a stop codon spanning fromnucleotide 982 through nucleotide 984 of SEQ ID NO:55.

[0143] This nucleic acid molecule was used as a template for asubsequent PCR reaction to obtain a full-length nucleic acid molecule.The PCR amplification was performed using Amplitaq DNA polymerase™ (PEApplied Biosystems Inc, Foster City, Calif.). The sequence of theforward primer was 5′ ACAGGTACCA TGCATCCTCA GCAGTTGGTC ATCGCCT 3′ (SEQID NO:87), and that of the reverse primer was 5′ CTAACTGCAG GACACGGATGCCCAG 3′ (SEQ ID NO:88). The PCR profile was as follows: one initialdenaturation step at 94° C. for 5 minutes; then 35 cycles of thefollowing: 94° C. for 30 seconds, then 50° C. for 30 seconds, then 72°C. for 90 seconds; followed by a final extension at 72° C. for 7minutes. This PCR product, the Fe IL-12p40 single chain subunitcontaining region of which is denoted nFeIL-12 p40₉₈₇ was found toencode a full-length feline IL-12 p40 single chain subunit protein. Thenucleotide sequence of the coding strand of nFeIL-12 p40₉₈₇ isrepresented herein as SEQ ID NO:29, and its complementary strand isdenoted by SEQ ID NO:31. Translation of SEQ ID NO:29 suggests thatnucleic acid molecule nFeIL-12p40₉₈₇ encodes a full-length PFeIL-12p40protein of about 329 amino acids, denoted herein as PFe IL-12p40₃₂₉, theamino acid sequence of which is presented in SEQ ID NO:30, assuming anopen reading frame having an initiation codon spanning from nucleotide 1through nucleotide 3 of SEQ ID NO:29 and a stop codon spanning fromnucleotide 985 through nucleotide 987 of SEQ ID NO:29. This PCR productwas digested with Kpn I and Pst I restriction enzymes (available fromNew England Biolabs) and cloned into the pBluescript-Linker plasmiddescribed in Example 3A. The resultant recombinant molecule is referredto as fep40-linker plasmid. There is a putative cleavage site on SEQ IDNO:30, yielding the coding region for a mature (i.e. lacking a signal orleader sequence) nFeIL-12p40₉₂₁, denoted herein as SEQ ID NO:26, withthe complement denoted SEQ ID NO:28. Translation of SEQ ID NO:26 yieldsa mature IL-12 p40 protein denoted PFeIL-12p40₃₀₇, also denoted hereinas SEQ ID NO:27.

[0144] C. A Feline IL-12 p35 nucleic acid molecule subunit was isolatedas follows: A cDNA mitogen library was prepared from cat peripheralblood lymphocytes stimulated with ConA for 4 hours as previouslydescribed in Example 1. An aliquot of this library was used as atemplate to isolate feline IL-12 p35 subunit by polymerase chainreaction (PCR). The PCR amplification was performed using Amplitaq DNApolymerase™ (PE Applied Biosystems Inc, Foster City, Calif.). Thesequence of the forward primer was 5′ ATGTGCCCGC CGCGTGGCC 3′ (SEQ IDNO:89), and that of the reverse primer was 5′ CTAGGAAGCA TTCAGATAGCTCATCAT 3′ (SEQ ID NO:90). The PCR profile was as follows: one initialdenaturation step at 94° C. for 5 minutes; then 43 cycles of thefollowing: 94° C. for 45 seconds, then 50° C. for 45 seconds, then 72°C. for 2 minutes; followed by a final extension at 72° C. for 7 minutes.PCR products were cloned into the TA-Cloning vector (available fromInvitrogen) and the nucleic acid molecules were sequenced as describedin Example 1. One of the sequenced PCR products contained 666nucleotides and was denoted herein as nFeIL-12-p35₆₆₆ with a codingstrand of SEQ ID NO:32, and a complementary strand of SEQ ID NO:34.Translation of SEQ ID NO:32 suggests that nucleic acid moleculenFeIL-12p35₆₆₆ encodes a full-length PFeIL-12p35 protein of about 222amino acids, denoted herein as PFe IL-12p35₂₂₂, the amino acid sequenceof which is presented in SEQ ID NO:33, assuming an open reading framehaving an initiation codon spanning from nucleotide 1 through nucleotide3 of SEQ ID NO:32 and a stop codon spanning from nucleotide 664 throughnucleotide 666 of SEQ ID NO:32. There is a putative cleavage site on SEQID NO:33, yielding the coding region for a mature (i.e. lacking a signalor leader sequence) nFeIL-12p35₅₉₁, denoted herein as SEQ ID NO:35, withthe complement denoted SEQ ID NO:37. Translation of SEQ ID NO:26 yieldsa mature IL-12 p35 protein denoted PFeIL 12p35₁₉₇, also denoted hereinas SEQ ID NO:36. SEQ ID NO:26 was digested with Sma I and Not Irestriction enzymes (available from New England Biolabs) and cloned intothe fep40-linker plasmid described in Example 3B digested with the sameenzymes. The resultant recombinant molecule is referred to asfep40-linker-p35mature plasmid.

[0145] D. The fep40-linker-p35mature plasmid contained a nucleic acidmolecule encoding a feline IL-12 single chain protein of the presentinvention inserted into the Kpn I and Not I sites of the pBluescriptbackbone. Nucleic acid molecule nFeIL-12₁₅₉₉ was sequenced as describedin Example 1. The nucleotide sequence of the coding strand ofnFeIL-12₁₅₉₉ is represented herein as SEQ ID NO:38, and that of thecomplementary strand is SEQ ID NO:40. Translation of the open readingframe in SEQ ID NO:38, suggests that nFeIL-12₁₅₉₉ encodes a proteincontaining 533 amino acids, referred to herein as pFeIL-12₅₃₃, with anamino acid sequence denoted by SEQ ID NO:39. The nucleic acid sequenceencoding the protein assumes an open reading frame in which the firstcodon spans from nucleotide 1 through 3 of SEQ ID NO:38 and the lastcodon spans from nucleotide 1597 nucleotide 1599 of SEQ ID NO:38. Theencoded protein has a predicted molecular weight of about 59.2 kDa. Theputative signal peptide cleavage site is between amino acid positions 22and 23 of the p40 subunit. Nucleic acid molecule nFeIL-12₁₅₃₃, whichencodes the mature protein contains a coding strand with SEQ ID NO:43,and a complementary strand with SEQ ID NO:45. The amino acid sequence ofthe mature protein, denoted herein as PFeIL-12₅₁₁ is SEQ ID NO:44 andthe mature protein has a predicted molecular weight of about 56.8 kDa.

[0146] Chinese hamster ovary (CHO) cells (available from ATCC,Rockville, Md.) were transiently transfected with fep40-linker-p35matureplasmid (containing SEQ ID NO:38) using techniques known to thoseskilled in the art, cell pellets and supernatants were harvested after48 hrs. Western analysis was performed on the cell pellets andsupernatant samples using a polyclonal antibody against human IL-12(available from Biosource International, Camarillo, Calif.). A faintband of the expected size (about 59.2 kDa) was detected in the cellpellet and in the supernatant, indicating that IL-12 is produced by thisconstruct at detectable levels.

EXAMPLE 4

[0147] This example describes the isolation and sequencing of nucleicacid molecules encoding canine IL-12 single chain proteins of thepresent invention.

[0148] A. A canine IL-12 p35 nucleic acid molecule subunit was isolatedas follows: A cDNA mitogen library was prepared from canine peripheralblood lymphocytes (PBLs) stimulated with ConA for 4 hours as describedin Example 1. Recombinant phage containing DNA encoding the p35 subunitwere identified by nucleic acid hybridization using a p32 radiolabeledprobe. The p35 probe (nCaIL-12p35TA) was generated by PCR of total RNA,prepared from ConA-stimulated PBLs in the following manner. The sequenceof the forward primer was 5′ CCATCCTGGT CCTGCTAAG C 3′ (SEQ ID NO:93)and the sequence of the reverse primer was 5′ CCATCTGGTA CATCTTCAAG TC3′ (SEQ ID NO:94). PCR amplification was performed using Amplitaq DNApolymerase™ (available from PE Applied Biosystems Inc.) using thefollowing profile: 95° C. for 2 minutes; then 30 cycles of 95° C. for 1minute, 55° C. for 1 minute, and 72° C. for 1 minute; and a finalextension at 72° C. for 10 minutes. The amplified DNA fragment waspurified with Qiagen gel purification kit, available from Qiagen, LaJolla, Calif.) and PCR products were cloned into the TA cloning vector(available from Invitrogen Corporation, Carlsbad, Calif.), and theresulting clones were sequenced using an ABI Prism™ Model 377 AutomaticDNA Sequencer (available from Perkin-Elmer Applied Biosystems Inc.,Foster City, Calif.). DNA sequencing reactions were performed usingPrism™ dRhodamine Terminator Cycle Sequencing Ready Reaction kits(available from PE Applied Biosystems Inc.). Phage DNA was permanentlycross-linked to the nitrocellulose sheets using a Stratalinker® UVcrosslinker (available from Stratagene). The plaque lifts werepre-hybridized in a solution of 6×SSC (20×SSC is 3.0 M NaCl and 0.3 Msodium citrate), 5×Denhardt's solution (50×SSC is 0.01 grams/milliliterFicoll, type 400; 0.01 g/ml polyvinylpyrrolidone; and 0.01 g/ml bovineserum albumin, fraction V, all available from Sigma, St. Louis, Mo.),0.5% sodium dodecyl sulfate (SDS), and 100 micrograms/ml denaturedsalmon sperm for 2 hours at 68° C. Denatured, radiolabeled probe wasadded to the pre-hybridization solution at a concentration of 1×10⁶cpm/ml and the hybridization continued for 18-24 hours at 68° C.Nonspecifically bound and unbound probe was removed by washing two timesin 2×SSC with 0.1% SDS, 30 minutes each at 68° C. and one time in 1×SSCwith 0.1% SDS, 60 minutes at 68° C. The hybridized plaque lifts wereexposed to Kodak x-ray film for approximately 18 hours. Positive phagewere plaque purified three times using the following hybridizationprotocol: phage plaques grown in solid top agar were lifted onto purenitrocellulose sheets (available from Schleicher & Schuell, Keene, N.H.)then denatured and neutralized by soaking the sheets in 0.5 N NaOH/1.5 MNaCl, followed by 0.5 M Tris-HCl pH7.4/1.5 M NaCl. pBluescript plasmid,containing a cDNA encoding the full-length canine IL-12 p35 subunit, wasexcised from plaque purified phage using the ExAssist™ helper phage(available from Stratagene) following the manufacturers' instructions.The nucleotide sequence of that cDNA, denoted herein as nCa IL-12p35₁₄₅₅ was verified by sequencing as described in Example 1. Thenucleic acid sequence of the coding strand of nCaIL-12p35₁₄₅₅represented as SEQ ID NO:104, and its complementary strand is SEQ IDNO:106. Translation of SEQ ID NO:104 suggests that nucleic acid moleculenCaIL-12p35₁₄₅₅ encodes an N-terminal portion of PCaIL-12p35 protein, ofabout 222 amino acids, denoted herein as PCa IL-12p35₂₂₂, the amino acidsequence of which is presented in SEQ ID NO:105, assuming an openreading frame having an initiation codon spanning from nucleotide 232through nucleotide 234 of SEQ ID NO:104 and a stop codon spanning fromnucleotide 895 through nucleotide 897 of SEQ ID NO:104.

[0149] Nucleic acid molecule nCaIL-12p35₁₄₅₅ was used as the template inPCR to obtain the coding region of the full-length form of canine IL-12p35 subunit. The sequence of the forward primer was 5′ AAAAAACCCGGGTATGTTCC AATGTTTCAA CCACTCCC 3′ (SEQ ID NO:95) and the sequence of thereverse primer was 5′ GCGGCCGCTC GAGTTAGGAA GAGTTCAAGT AGGACATCATTCTATTGATG G 3′ (SEQ ID NO:96). PCR was performed using Pfu DNApolymerase (available from Stratagene) as follows: 95° C. for 45seconds; then 25 cycles of 95° C. for 45 seconds, 55° C. for 45 seconds,72° C. for 1 minute; followed by a final extension at 72° C. for 10minutes. The PCR product contains the nucleic acid sequence of canineIL-12 p35 subunit which encodes a full-length canine IL-12 p35 subunitprotein. The nucleotide sequence of the coding strand of nCaIL-12p35₆₆₆is represented herein as SEQ ID NO:46 and its complementary strand isdenoted SEQ ID NO:48. Translation of SEQ ID NO:46 suggests that nucleicacid molecule nCaIL-12p35₆₆₆ encodes a mature PCaIL-12p35 single chainprotein of about 222 amino acids, denoted herein as PCaIL-12p35₂₂₂, theamino acid sequence of which is presented in SEQ ID NO:47, assuming anopen reading frame having an initiation codon spanning from nucleotide 1through nucleotide 3 of SEQ ID NO:46 and a stop codon spanning fromnucleotide 589 through nucleotide 591 of SEQ ID NO:46. The codingsequence for the mature polypeptide is encoded by SEQ ID NO:46, thecoding region for a mature (i.e. lacking a signal or leader sequence)nCaIL-12p35₅₉₁, denoted herein as SEQ ID NO:49, with the complementdenoted SEQ ID NO:51. Translation of SEQ ID NO:49 yields a mature IL-12p35 protein denoted PCaIL-12p35₁₉₇, also denoted herein as SEQ ID NO:50.nCaIL-12p35₅₉₁ was digested with SmaI and XhoI restriction endonucleases(available from New England Biolabs) and ligated into thepBluescript-Linker plasmid described in Example 3A digested with thesame enzymes. The resultant recombinant molecule is referred to ascalinker-p35mature plasmid.

[0150] B. Canine IL-12 p40 nucleic acid molecule subunit was isolated asfollows: A cDNA mitogen library was prepared from canine peripheralblood lymphocytes stimulated with ConA for 4 hours as described inExample 1. Recombinant phage containing DNA encoding the p40 subunitwere identified by nucleic acid hybridization using a p³² radiolabeledprobe. The p40 probe (nCaIL-12p40TA) was generated by PCR of total RNA,prepared from ConA stimulated PBLs in the following manner. The sequenceof the forward primer was 5′ CTTAAAGGAA CAGAAAGAAT CC 3′ (SEQ ID NO:97)and the sequence of the reverse primer was 5′ GGTATTCCCA GCTGACCTC 3′(SEQ ID NO:98). PCR amplification was performed using Amplitaq DNApolymerase™ (available from PE Applied Biosystems Inc.) using thefollowing profile: 95° C. for 2 minutes; then 30 cycles of 95° C. for 1minute, 55° C. for 1 minute, and 72° C. for 1 m and a final extension at72° C. for 10 minutes. The amplified DNA fragment was purified withQiagen gel purification kit, available from Qiagen, La Jolla, Calif.)and PCR products were cloned into the TA cloning vector (available fromInvitrogen Corporation, Carlsbad, Calif.), and the resulting clones weresequenced using an ABI Prism™ Model 377 Automatic DNA Sequencer(available from Perkin-Elmer Applied Biosystems Inc., Foster City,Calif.). DNA sequencing reactions were performed using Prism™ dRhodamineTerminator Cycle Sequencing Ready Reaction kits (available from PEApplied Biosystems Inc.). Phage DNA was permanently cross-linked to thenitrocellulose sheets using a Stratalinker® UV crosslinker (availablefrom Stratagene). The plaque lifts were pre-hybridized in a solution of6×SSC (20×SSC is 3.0 M NaCl and 0.3 M sodium citrate), 5×Denhardt'ssolution (50×SSC is 0.01 grams/milliliter Ficoll, type 400; 0.10 g/mlpolyvinylpyrrolidone; and 0.01 g/ml bovine serum albumin, fraction V,all available from Sigma, St. Louis, Mo.), 0.5% sodium dodecyl sulfate(SDS), and 100 micrograms/ml denatured salmon sperm for 2 hours at 68°C. Denatured, radiolabeled probe was added to the pre-hybridizationsolution at a concentration of 1×10⁶ cpm/ml and the hybridizationcontinued for 18-24 hours at 68° C. Nonspecifically bound and unboundprobe was removed by washing two times in 2×SSC with 0.1% SDS, 30minutes each at 68° C. and one time in 1×SSC with 0.1% SDS, 60 minutesat 68° C. The hybridized plaque lifts were exposed to Kodak x-ray filmfor approximately 18 hours. Positive phage were plaque purified threetimes using the following hybridization protocol: phage plaques grown insolid top agar were lifted onto pure nitrocellulose sheets (availablefrom Schleicher & Schuell, Keene, N.H.) then denatured and neutralizedby soaking the sheets in 0.5 N NaOH/1.5 M NaCl, followed by 0.5 MTris-HCl pH7.4/1.5 M NaCl. pBluescript plasmid, containing a cDNAencoding the full-length canine IL-12 p40 subunit, was excised fromplaque purified phage using the ExAssist™ helper phage (available fromStratagene) following the manufacturers' instructions. The nucleotidesequence of that cDNA, denoted herein as nCaIL-12p40₂₂₆₇ was verified bysequencing as described in Example 1. The nucleic acid sequence of thecoding strand of nCaIL-12p40₂₂₆₇ represented as SEQ ID NO:107, and itscomplementary strand is SEQ ID NO:109. Translation of SEQ ID NO:107suggests that nucleic acid molecule nCaIL-12p40₂₂₆₇ encodes anPCaIL-12p40 protein, of about 329 amino acids, denoted herein as PCaIL-12p40₃₂₉, the amino acid sequence of which is presented in SEQ IDNO:108, assuming an open reading frame having an initiation codonspanning from nucleotide 154 through nucleotide 156 of SEQ ID NO:107 anda stop codon spanning from nucleotide 1138 through nucleotide 1140 ofSEQ ID NO:107. Full length canine IL-12 p40 nucleic acid molecule wasisolated as follows: A plasmid containing full-length canine IL-12 p40nucleic acid molecule subunit (pCaIL-12p40) was used as a template tosub-clone canine IL-12 p40 subunit by polymerase chain reaction (PCR).PCR amplification was performed using Amplitaq DNA polymerase™(available from PE Applied Biosystems Inc.). The sequence of the forwardprimer (Dog p40 KpnFor) was 5′ CATAGGTACC ATGCACCCTC AGCAGTTGGT CATCTCC3′ (SEQ ID NO:99), and that of the reverse primer (Dog p40 NsiRev) was5′ ATCTAAATGC ATGACACAGA TGCCCAGTC 3′ (SEQ ID NO:100). The PCR profilewas as follows: one initial denaturation step at 94° C. for 5 minutes;then 35 cycles of the following: 94° C. for 30 seconds, then 55° C. for30 seconds, then 72° C. for 2 minutes; followed by a final extension at72° C. for 7 minutes. The PCR product contains the nucleic acid sequenceof canine IL-12 p40 subunit along with its native signal sequence whichencodes a canine full-length IL-1-2 p40 subunit protein. The nucleotidesequence of the coding strand of nCaIL-12 P40₉₈₇, is represented hereinas SEQ ID NO:58 and its complementary strand is denoted SEQ ID NO:60.Translation of the open reading frame in SEQ ID NO:58, suggests thatcanine IL-12 p40 subunit encodes a protein containing 329 amino acids,referred to herein as PCaIL-12 p40₃₂₉ with an amino acid sequencedenoted by SEQ ID NO:59. The resulting recombinant molecule is referredto as cap40-linker plasmid. The cap40-linker plasmid was digested withKpn I and Pst I restriction enzymes (available from New England Biolabs)to remove the region encoding canine p40 mature protein. The PCR productcontaining the full-length canine p40 subunit (nCaIL-12 p40₉₈₇) wasdigested with Kpn I and Nsi I restriction enzymes (available from NewEngland Biolabs) and cloned into this digested plasmid. The codingsequence for the mature canine IL-12 p40 polypeptide is encoded by SEQID NO:52, the coding region for a mature (i.e. lacking a signal orleader sequence) nCaIL-12p40₉₂₁, with the complement denoted SEQ IDNO:53. Translation of SEQ ID NO:52 yields a mature IL-12 p40 proteindenoted PCaIL-12p35₃₀₇, also denoted herein as SEQ ID N0:53.nCaIL-12p40₉₂₁ was digested with SmaI and XhoI restriction endonucleases(available from New England Biolabs) and ligated into thepBluescript-Linker plasmid described in Example 3A digested with thesame enzymes.

[0151] The resulting plasmid contains a nucleic acid molecule encoding acanine IL-12 single chain cloned at the Kpn I and Not I site into thepBluescript backbone. The complete canine IL-12 single chain insert wassequenced as described in Example 1. The nucleotide sequence of thecoding strand of nCaIL-12-single chain₁₅₉₉ is represented herein as SEQID NO:61, and its complement is denoted by SEQ ID NO:63. Translation ofthe open readings frame in SEQ ID NO:61, denoted here as nCaIL-12₁₅₉₉with a SEQ ID NO:64 suggests that canine IL-12-single chain encodes aprotein containing 533 amino acids, referred to herein as PCaIL-12₅₃₃,with an amino acid sequence denoted by SEQ ID NO:62, assuming an openreading frame in which the first codon spans from nucleotide 1 through 3of SEQ ID NO:61 and the last codon spans from nucleotide 1597 nucleotide1599 of SEQ ID NO:61. The encoded protein has a predicted molecularweight of about 59.2 kDa for the precursor protein, and about 56.8 kDafor the mature protein. The putative signal peptide cleavage site isbetween amino acid positions 22 and 23 of the canine p40 subunitprotein. Nucleic acid molecule nCaIL-12₁₅₃₃, which encodes the matureprotein contains a coding strand with SEQ ID NO:66, and a complementarystrand with SEQ ID NO:68. The amino acid sequence of the mature protein,denoted herein as pCaIL-12₅₁₁, is SEQ ID NO:67 and the mature proteinhas a predicted molecular weight of about 56.8 kDa.

[0152] Chinese hamster ovary (CHO) cells (available from ATCC,Rockville, Md.) were transiently transfected with cap40-linker-p35matureplasmid using techniques known to those skilled in the art and cellpellets and supernatants were harvested after 48 hrs. Western analysiswas performed on the cell pellets and supernatant samples using apolyclonal antibody against human IL-12 (available from BiosourceInternational, Camarillo, Calif.). A faint band of the expected size(about 59.2 kDa) was detected in the cell pellet and in the supernatant,indicating that IL-12 is produced by this construct at detectablelevels.

1 111 1 514 DNA Felis catus CDS (114)..(512) misc_feature (470)..(470) n= unknown at position 470 Xaa = unknown at position 119 1 gctaaaggcgctcctgccac cttctgccat ctacacagct caggaaaaga aagggacctc 60 aaaccttccagatcccttcc tctcttagga aactattgag cacagggata aag atg 116 Met 1 act gctata cca gta gat gat tgc atc aac ttt gtg gga atg aaa ttt 164 Thr Ala IlePro Val Asp Asp Cys Ile Asn Phe Val Gly Met Lys Phe 5 10 15 att gac aataca ctt tac ttt gta gct gac agt gat gaa aac ctg gaa 212 Ile Asp Asn ThrLeu Tyr Phe Val Ala Asp Ser Asp Glu Asn Leu Glu 20 25 30 aca gat tac tttggc aag ctt gaa cat aaa ctc tca atc tta cga aac 260 Thr Asp Tyr Phe GlyLys Leu Glu His Lys Leu Ser Ile Leu Arg Asn 35 40 45 ttg aac gac caa gttctc ttc att aac cag gga gat caa cct gtg ttt 308 Leu Asn Asp Gln Val LeuPhe Ile Asn Gln Gly Asp Gln Pro Val Phe 50 55 60 65 gag gat atg cct gattct gac tgt aca gat aat gca ccc cgg act gaa 356 Glu Asp Met Pro Asp SerAsp Cys Thr Asp Asn Ala Pro Arg Thr Glu 70 75 80 ttt atc ata tat atg tataaa gat agc ctc act aga ggt ctg gca gta 404 Phe Ile Ile Tyr Met Tyr LysAsp Ser Leu Thr Arg Gly Leu Ala Val 85 90 95 acc atc tct gtg aat tat aagacc atg tct act ctc tcc tgt gag aac 452 Thr Ile Ser Val Asn Tyr Lys ThrMet Ser Thr Leu Ser Cys Glu Asn 100 105 110 aaa att att tcc ttt aan ggaatg agt cct cct gag agt atc aat gat 500 Lys Ile Ile Ser Phe Xaa Gly MetSer Pro Pro Glu Ser Ile Asn Asp 115 120 125 gaa gga aat gac at 514 GluGly Asn Asp 130 2 133 PRT Felis catus misc_feature (119)..(119) The′Xaa′ at location 119 stands for Lys, or Asn. 2 Met Thr Ala Ile Pro ValAsp Asp Cys Ile Asn Phe Val Gly Met Lys 1 5 10 15 Phe Ile Asp Asn ThrLeu Tyr Phe Val Ala Asp Ser Asp Glu Asn Leu 20 25 30 Glu Thr Asp Tyr PheGly Lys Leu Glu His Lys Leu Ser Ile Leu Arg 35 40 45 Asn Leu Asn Asp GlnVal Leu Phe Ile Asn Gln Gly Asp Gln Pro Val 50 55 60 Phe Glu Asp Met ProAsp Ser Asp Cys Thr Asp Asn Ala Pro Arg Thr 65 70 75 80 Glu Phe Ile IleTyr Met Tyr Lys Asp Ser Leu Thr Arg Gly Leu Ala 85 90 95 Val Thr Ile SerVal Asn Tyr Lys Thr Met Ser Thr Leu Ser Cys Glu 100 105 110 Asn Lys IleIle Ser Phe Xaa Gly Met Ser Pro Pro Glu Ser Ile Asn 115 120 125 Asp GluGly Asn Asp 130 3 514 DNA Felis catus misc_feature (45)..(45) n =unknown at position 45 3 atgtcatttc cttcatcatt gatactctca ggaggactcattccnttaaa ggaaataatt 60 ttgttctcac aggagagagt agacatggtc ttataattcacagagatggt tactgccaga 120 cctctagtga ggctatcttt atacatatat atgataaattcagtccgggg tgcattatct 180 gtacagtcag aatcaggcat atcctcaaac acaggttgatctccctggtt aatgaagaga 240 acttggtcgt tcaagtttcg taagattgag agtttatgttcaagcttgcc aaagtaatct 300 gtttccaggt tttcatcact gtcagctaca aagtaaagtgtattgtcaat aaatttcatt 360 cccacaaagt tgatgcaatc atctactggt atagcagtcatctttatccc tgtgctcaat 420 agtttcctaa gagaggaagg gatctggaag gtttgaggtccctttctttt cctgagctgt 480 gtagatggca gaaggtggca ggagcgcctt tagc 514 4502 DNA Felis catus CDS (3)..(464) misc_feature (126)..(126) n = unknownat position 126 Xaa = unknown at position 42 4 gc aag ctt gaa cat aaactc tca atc tta cga aac ttg aac gac caa 47 Lys Leu Glu His Lys Leu SerIle Leu Arg Asn Leu Asn Asp Gln 1 5 10 15 gtt ctc ttc att aac cag ggagat caa cct gtg ttt gag gat atg cct 95 Val Leu Phe Ile Asn Gln Gly AspGln Pro Val Phe Glu Asp Met Pro 20 25 30 gat tct gac tgt aca gat aat gcaccc cgg nct gaa ttt atc ata tat 143 Asp Ser Asp Cys Thr Asp Asn Ala ProArg Xaa Glu Phe Ile Ile Tyr 35 40 45 atg tat aaa gat agc ctc act aga ggtctg gca gta acc atc tct gtg 191 Met Tyr Lys Asp Ser Leu Thr Arg Gly LeuAla Val Thr Ile Ser Val 50 55 60 aat tat aag acc atg tct act ctc tcc tgtgag aac aaa att att tcc 239 Asn Tyr Lys Thr Met Ser Thr Leu Ser Cys GluAsn Lys Ile Ile Ser 65 70 75 ttt aag gaa atg agt cct cct gag agt atc aatgat gaa gga aat gac 287 Phe Lys Glu Met Ser Pro Pro Glu Ser Ile Asn AspGlu Gly Asn Asp 80 85 90 95 atc ata ttc ttt cag aga agt gtt cca gga catgat gat aag ata caa 335 Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His AspAsp Lys Ile Gln 100 105 110 ttt gag tct tca ttg tac aag ggg tac ttt ctagct tgt gaa aaa gag 383 Phe Glu Ser Ser Leu Tyr Lys Gly Tyr Phe Leu AlaCys Glu Lys Glu 115 120 125 aaa gat ctt ttc aaa ctc att ttg aaa aaa aaggat gaa aat ggg gat 431 Lys Asp Leu Phe Lys Leu Ile Leu Lys Lys Lys AspGlu Asn Gly Asp 130 135 140 aag tcc ata atg ttc act gtt caa aac aag aattagatattaa aattgcataa 484 Lys Ser Ile Met Phe Thr Val Gln Asn Lys Asn145 150 tttgaaaaaa aaaaaaaa 502 5 154 PRT Felis catus misc_feature(42)..(42) The ′Xaa′ at location 42 stands for Thr, Ala, Pro, or Ser. 5Lys Leu Glu His Lys Leu Ser Ile Leu Arg Asn Leu Asn Asp Gln Val 1 5 1015 Leu Phe Ile Asn Gln Gly Asp Gln Pro Val Phe Glu Asp Met Pro Asp 20 2530 Ser Asp Cys Thr Asp Asn Ala Pro Arg Xaa Glu Phe Ile Ile Tyr Met 35 4045 Tyr Lys Asp Ser Leu Thr Arg Gly Leu Ala Val Thr Ile Ser Val Asn 50 5560 Tyr Lys Thr Met Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser Phe 65 7075 80 Lys Glu Met Ser Pro Pro Glu Ser Ile Asn Asp Glu Gly Asn Asp Ile 8590 95 Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asp Lys Ile Gln Phe100 105 110 Glu Ser Ser Leu Tyr Lys Gly Tyr Phe Leu Ala Cys Glu Lys GluLys 115 120 125 Asp Leu Phe Lys Leu Ile Leu Lys Lys Lys Asp Glu Asn GlyAsp Lys 130 135 140 Ser Ile Met Phe Thr Val Gln Asn Lys Asn 145 150 6502 DNA Felis catus misc_feature (377)..(377) n = unknown at position377 6 tttttttttt ttttcaaatt atgcaatttt aatatctaat tcttgttttg aacagtgaac60 attatggact tatccccatt ttcatccttt tttttcaaaa tgagtttgaa aagatctttc 120tctttttcac aagctagaaa gtaccccttg tacaatgaag actcaaattg tatcttatca 180tcatgtcctg gaacacttct ctgaaagaat atgatgtcat ttccttcatc attgatactc 240tcaggaggac tcatttcctt aaaggaaata attttgttct cacaggagag agtagacatg 300gtcttataat tcacagagat ggttactgcc agacctctag tgaggctatc tttatacata 360tatatgataa attcagnccg gggtgcatta tctgtacagt cagaatcagg catatcctca 420aacacaggtt gatctccctg gttaatgaag agaacttggt cgttcaagtt tcgtaagatt 480gagagtttat gttcaagctt gc 502 7 607 DNA Felis catus CDS (24)..(599) 7aactattgag cacagggata aag atg act gct ata cca gta gat gat tgc atc 53 MetThr Ala Ile Pro Val Asp Asp Cys Ile 1 5 10 aac ttt gtg gga atg aaa tttatt gac aat aca ctt tac ttt gta gct 101 Asn Phe Val Gly Met Lys Phe IleAsp Asn Thr Leu Tyr Phe Val Ala 15 20 25 gac agt gat gaa aac ctg gaa acagat tac ttt ggc aag ctt gaa cat 149 Asp Ser Asp Glu Asn Leu Glu Thr AspTyr Phe Gly Lys Leu Glu His 30 35 40 aaa ctc tca atc tta cga aac ttg aacgac caa gtt ctc ttc att aac 197 Lys Leu Ser Ile Leu Arg Asn Leu Asn AspGln Val Leu Phe Ile Asn 45 50 55 cag gga gat caa cct gtg ttt gag gat atgcct gat tct gac tgt aca 245 Gln Gly Asp Gln Pro Val Phe Glu Asp Met ProAsp Ser Asp Cys Thr 60 65 70 gat aat gca ccc cgg act gaa ttt atc ata tatatg tat aaa gat agc 293 Asp Asn Ala Pro Arg Thr Glu Phe Ile Ile Tyr MetTyr Lys Asp Ser 75 80 85 90 ctc act aga ggt ctg gca gta acc atc tct gtgaat tat aag acc atg 341 Leu Thr Arg Gly Leu Ala Val Thr Ile Ser Val AsnTyr Lys Thr Met 95 100 105 tct act ctc tcc tgt gag aac aaa att att tccttt aag gaa atg agt 389 Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser PheLys Glu Met Ser 110 115 120 cct cct gag agt atc aat gat gaa gga aat gacatc ata ttc ttt cag 437 Pro Pro Glu Ser Ile Asn Asp Glu Gly Asn Asp IleIle Phe Phe Gln 125 130 135 aga agt gtt cca gga cat gat gat aag ata caattt gag tct tca ttg 485 Arg Ser Val Pro Gly His Asp Asp Lys Ile Gln PheGlu Ser Ser Leu 140 145 150 tac aag ggg tac ttt cta gct tgt gaa aaa gagaaa gat ctt ttc aaa 533 Tyr Lys Gly Tyr Phe Leu Ala Cys Glu Lys Glu LysAsp Leu Phe Lys 155 160 165 170 ctc att ttg aaa aaa aag gat gaa aat ggggat aag tcc ata atg ttc 581 Leu Ile Leu Lys Lys Lys Asp Glu Asn Gly AspLys Ser Ile Met Phe 175 180 185 act gtt caa aac aag aat tagatatt 607 ThrVal Gln Asn Lys Asn 190 8 192 PRT Felis catus 8 Met Thr Ala Ile Pro ValAsp Asp Cys Ile Asn Phe Val Gly Met Lys 1 5 10 15 Phe Ile Asp Asn ThrLeu Tyr Phe Val Ala Asp Ser Asp Glu Asn Leu 20 25 30 Glu Thr Asp Tyr PheGly Lys Leu Glu His Lys Leu Ser Ile Leu Arg 35 40 45 Asn Leu Asn Asp GlnVal Leu Phe Ile Asn Gln Gly Asp Gln Pro Val 50 55 60 Phe Glu Asp Met ProAsp Ser Asp Cys Thr Asp Asn Ala Pro Arg Thr 65 70 75 80 Glu Phe Ile IleTyr Met Tyr Lys Asp Ser Leu Thr Arg Gly Leu Ala 85 90 95 Val Thr Ile SerVal Asn Tyr Lys Thr Met Ser Thr Leu Ser Cys Glu 100 105 110 Asn Lys IleIle Ser Phe Lys Glu Met Ser Pro Pro Glu Ser Ile Asn 115 120 125 Asp GluGly Asn Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His 130 135 140 AspAsp Lys Ile Gln Phe Glu Ser Ser Leu Tyr Lys Gly Tyr Phe Leu 145 150 155160 Ala Cys Glu Lys Glu Lys Asp Leu Phe Lys Leu Ile Leu Lys Lys Lys 165170 175 Asp Glu Asn Gly Asp Lys Ser Ile Met Phe Thr Val Gln Asn Lys Asn180 185 190 9 576 DNA Felis catus 9 atgactgcta taccagtaga tgattgcatcaactttgtgg gaatgaaatt tattgacaat 60 acactttact ttgtagctga cagtgatgaaaacctggaaa cagattactt tggcaagctt 120 gaacataaac tctcaatctt acgaaacttgaacgaccaag ttctcttcat taaccaggga 180 gatcaacctg tgtttgagga tatgcctgattctgactgta cagataatgc accccggact 240 gaatttatca tatatatgta taaagatagcctcactagag gtctggcagt aaccatctct 300 gtgaattata agaccatgtc tactctctcctgtgagaaca aaattatttc ctttaaggaa 360 atgagtcctc ctgagagtat caatgatgaaggaaatgaca tcatattctt tcagagaagt 420 gttccaggac atgatgataa gatacaatttgagtcttcat tgtacaaggg gtactttcta 480 gcttgtgaaa aagagaaaga tcttttcaaactcattttga aaaaaaagga tgaaaatggg 540 gataagtcca taatgttcac tgttcaaaacaagaat 576 10 607 DNA Felis catus 10 aatatctaat tcttgttttg aacagtgaacattatggact tatccccatt ttcatccttt 60 tttttcaaaa tgagtttgaa aagatctttctctttttcac aagctagaaa gtaccccttg 120 tacaatgaag actcaaattg tatcttatcatcatgtcctg gaacacttct ctgaaagaat 180 atgatgtcat ttccttcatc attgatactctcaggaggac tcatttcctt aaaggaaata 240 attttgttct cacaggagag agtagacatggtcttataat tcacagagat ggttactgcc 300 agacctctag tgaggctatc tttatacatatatatgataa attcagtccg gggtgcatta 360 tctgtacagt cagaatcagg catatcctcaaacacaggtt gatctccctg gttaatgaag 420 agaacttggt cgttcaagtt tcgtaagattgagagtttat gttcaagctt gccaaagtaa 480 tctgtttcca ggttttcatc actgtcagctacaaagtaaa gtgtattgtc aataaatttc 540 attcccacaa agttgatgca atcatctactggtatagcag tcatctttat ccctgtgctc 600 aatagtt 607 11 471 DNA Felis catusCDS (1)..(471) 11 tac ttt ggc aag ctt gaa cat aaa ctc tca atc tta cgaaac ttg aac 48 Tyr Phe Gly Lys Leu Glu His Lys Leu Ser Ile Leu Arg AsnLeu Asn 1 5 10 15 gac caa gtt ctc ttc att aac cag gga gat caa cct gtgttt gag gat 96 Asp Gln Val Leu Phe Ile Asn Gln Gly Asp Gln Pro Val PheGlu Asp 20 25 30 atg cct gat tct gac tgt aca gat aat gca ccc cgg act gaattt atc 144 Met Pro Asp Ser Asp Cys Thr Asp Asn Ala Pro Arg Thr Glu PheIle 35 40 45 ata tat atg tat aaa gat agc ctc act aga ggt ctg gca gta accatc 192 Ile Tyr Met Tyr Lys Asp Ser Leu Thr Arg Gly Leu Ala Val Thr Ile50 55 60 tct gtg aat tat aag acc atg tct act ctc tcc tgt gag aac aaa att240 Ser Val Asn Tyr Lys Thr Met Ser Thr Leu Ser Cys Glu Asn Lys Ile 6570 75 80 att tcc ttt aag gaa atg agt cct cct gag agt atc aat gat gaa gga288 Ile Ser Phe Lys Glu Met Ser Pro Pro Glu Ser Ile Asn Asp Glu Gly 8590 95 aat gac atc ata ttc ttt cag aga agt gtt cca gga cat gat gat aag336 Asn Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asp Lys 100105 110 ata caa ttt gag tct tca ttg tac aag ggg tac ttt cta gct tgt gaa384 Ile Gln Phe Glu Ser Ser Leu Tyr Lys Gly Tyr Phe Leu Ala Cys Glu 115120 125 aaa gag aaa gat ctt ttc aaa ctc att ttg aaa aaa aag gat gaa aat432 Lys Glu Lys Asp Leu Phe Lys Leu Ile Leu Lys Lys Lys Asp Glu Asn 130135 140 ggg gat aag tcc ata atg ttc act gtt caa aac aag aat 471 Gly AspLys Ser Ile Met Phe Thr Val Gln Asn Lys Asn 145 150 155 12 157 PRT Feliscatus 12 Tyr Phe Gly Lys Leu Glu His Lys Leu Ser Ile Leu Arg Asn Leu Asn1 5 10 15 Asp Gln Val Leu Phe Ile Asn Gln Gly Asp Gln Pro Val Phe GluAsp 20 25 30 Met Pro Asp Ser Asp Cys Thr Asp Asn Ala Pro Arg Thr Glu PheIle 35 40 45 Ile Tyr Met Tyr Lys Asp Ser Leu Thr Arg Gly Leu Ala Val ThrIle 50 55 60 Ser Val Asn Tyr Lys Thr Met Ser Thr Leu Ser Cys Glu Asn LysIle 65 70 75 80 Ile Ser Phe Lys Glu Met Ser Pro Pro Glu Ser Ile Asn AspGlu Gly 85 90 95 Asn Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His AspAsp Lys 100 105 110 Ile Gln Phe Glu Ser Ser Leu Tyr Lys Gly Tyr Phe LeuAla Cys Glu 115 120 125 Lys Glu Lys Asp Leu Phe Lys Leu Ile Leu Lys LysLys Asp Glu Asn 130 135 140 Gly Asp Lys Ser Ile Met Phe Thr Val Gln AsnLys Asn 145 150 155 13 471 DNA Felis catus 13 attcttgttt tgaacagtgaacattatgga cttatcccca ttttcatcct tttttttcaa 60 aatgagtttg aaaagatctttctctttttc acaagctaga aagtacccct tgtacaatga 120 agactcaaat tgtatcttatcatcatgtcc tggaacactt ctctgaaaga atatgatgtc 180 atttccttca tcattgatactctcaggagg actcatttcc ttaaaggaaa taattttgtt 240 ctcacaggag agagtagacatggtcttata attcacagag atggttactg ccagacctct 300 agtgaggcta tctttatacatatatatgat aaattcagtc cggggtgcat tatctgtaca 360 gtcagaatca ggcatatcctcaaacacagg ttgatctccc tggttaatga agagaacttg 420 gtcgttcaag tttcgtaagattgagagttt atgttcaagc ttgccaaagt a 471 14 1233 DNA Felis catus CDS(1)..(1230) 14 atg gcc gac aag gtc ctg aag gag aag agg aag cag ttc atcaac tca 48 Met Ala Asp Lys Val Leu Lys Glu Lys Arg Lys Gln Phe Ile AsnSer 1 5 10 15 gtc ggc atg ggg acg gtc aac ggc ttg ctg gat gaa ctc tttgag aaa 96 Val Gly Met Gly Thr Val Asn Gly Leu Leu Asp Glu Leu Phe GluLys 20 25 30 aac gtg ctg aac cag gag gag atg gag aga gta aaa tgt gaa aacgct 144 Asn Val Leu Asn Gln Glu Glu Met Glu Arg Val Lys Cys Glu Asn Ala35 40 45 acc gtt atg gac aag gcc cga gct ctg atc gac agc gtc ctg cgg aaa192 Thr Val Met Asp Lys Ala Arg Ala Leu Ile Asp Ser Val Leu Arg Lys 5055 60 ggg cca cgg gcg tgc cag atc ttt atc tgt cac atc tgt gag gaa gac240 Gly Pro Arg Ala Cys Gln Ile Phe Ile Cys His Ile Cys Glu Glu Asp 6570 75 80 acc cac ctt gca gag acg ctg ggg ctc tcc tca agc cca caa tct gga288 Thr His Leu Ala Glu Thr Leu Gly Leu Ser Ser Ser Pro Gln Ser Gly 8590 95 aat tct cag aac acc acg gac tct gaa gta gcg ttt cct cct ctt cca336 Asn Ser Gln Asn Thr Thr Asp Ser Glu Val Ala Phe Pro Pro Leu Pro 100105 110 gcc agc gtg aat aac atg cct ggg ccg gct gag cca gaa gaa tct gta384 Ala Ser Val Asn Asn Met Pro Gly Pro Ala Glu Pro Glu Glu Ser Val 115120 125 gat gct ctc aag ctt tgt cct cgt gaa aac ttc gtg aaa ctg tgt aaa432 Asp Ala Leu Lys Leu Cys Pro Arg Glu Asn Phe Val Lys Leu Cys Lys 130135 140 cag agg gct gaa gag atc tac cca ata aag gag aga aag gat cgt act480 Gln Arg Ala Glu Glu Ile Tyr Pro Ile Lys Glu Arg Lys Asp Arg Thr 145150 155 160 cgt ctg gct ctc atc ata tgc aat acg acg ttc gat cat ctt tctctc 528 Arg Leu Ala Leu Ile Ile Cys Asn Thr Thr Phe Asp His Leu Ser Leu165 170 175 agg aag ggg gct gac ctt gac gtt gca ggg atg agg agg ctg cttaca 576 Arg Lys Gly Ala Asp Leu Asp Val Ala Gly Met Arg Arg Leu Leu Thr180 185 190 gac ctt ggc tac agt gtg cac ata aaa gag gaa ctc act gct aaggac 624 Asp Leu Gly Tyr Ser Val His Ile Lys Glu Glu Leu Thr Ala Lys Asp195 200 205 atg gaa tca gag ctg agg gca ttt gct gcc cgt cca gag cac aagtcc 672 Met Glu Ser Glu Leu Arg Ala Phe Ala Ala Arg Pro Glu His Lys Ser210 215 220 tcg gac agc aca ttc ctg gtg ttc atg tct cat ggc atc ctg agtgga 720 Ser Asp Ser Thr Phe Leu Val Phe Met Ser His Gly Ile Leu Ser Gly225 230 235 240 atc tgt ggg acg aag tac agc gct gaa gga gac cca gat gtattg gct 768 Ile Cys Gly Thr Lys Tyr Ser Ala Glu Gly Asp Pro Asp Val LeuAla 245 250 255 tat gac acc atc ttc cag att ttc aac aac cgc aac tgc cttagt cta 816 Tyr Asp Thr Ile Phe Gln Ile Phe Asn Asn Arg Asn Cys Leu SerLeu 260 265 270 aag gac aag ccc aag gtc atc atc gtc cag gcc tgc aga ggtgaa aat 864 Lys Asp Lys Pro Lys Val Ile Ile Val Gln Ala Cys Arg Gly GluAsn 275 280 285 ttg ggg gaa ctg ttg atc agt gac tct cca gcg gcc cca atggac agc 912 Leu Gly Glu Leu Leu Ile Ser Asp Ser Pro Ala Ala Pro Met AspSer 290 295 300 act tca cag atg ggt agc agc ctt tca cag gtg ggt gac aaccta gag 960 Thr Ser Gln Met Gly Ser Ser Leu Ser Gln Val Gly Asp Asn LeuGlu 305 310 315 320 gac gac gcc att tac aag gtc cac gtg gag aag gac ttcatc gct ttc 1008 Asp Asp Ala Ile Tyr Lys Val His Val Glu Lys Asp Phe IleAla Phe 325 330 335 tgc tcc tcg acc cca cat cat gtg tct tgg aga gac gtgaac aag gga 1056 Cys Ser Ser Thr Pro His His Val Ser Trp Arg Asp Val AsnLys Gly 340 345 350 tct ctc ttc att aca caa ctc atc acg tgc ttc caa aagtat tcg tgg 1104 Ser Leu Phe Ile Thr Gln Leu Ile Thr Cys Phe Gln Lys TyrSer Trp 355 360 365 tgc ttt cat ctg gag gaa gta ttt cgg aag gta caa cagtca ttt gaa 1152 Cys Phe His Leu Glu Glu Val Phe Arg Lys Val Gln Gln SerPhe Glu 370 375 380 aaa cca aat gtt aga gcc cag atg ccc acc att gaa cgacta tcc atg 1200 Lys Pro Asn Val Arg Ala Gln Met Pro Thr Ile Glu Arg LeuSer Met 385 390 395 400 aca aga tgt ttc tac ctc ttc cca gga cat taa 1233Thr Arg Cys Phe Tyr Leu Phe Pro Gly His 405 410 15 410 PRT Felis catus15 Met Ala Asp Lys Val Leu Lys Glu Lys Arg Lys Gln Phe Ile Asn Ser 1 510 15 Val Gly Met Gly Thr Val Asn Gly Leu Leu Asp Glu Leu Phe Glu Lys 2025 30 Asn Val Leu Asn Gln Glu Glu Met Glu Arg Val Lys Cys Glu Asn Ala 3540 45 Thr Val Met Asp Lys Ala Arg Ala Leu Ile Asp Ser Val Leu Arg Lys 5055 60 Gly Pro Arg Ala Cys Gln Ile Phe Ile Cys His Ile Cys Glu Glu Asp 6570 75 80 Thr His Leu Ala Glu Thr Leu Gly Leu Ser Ser Ser Pro Gln Ser Gly85 90 95 Asn Ser Gln Asn Thr Thr Asp Ser Glu Val Ala Phe Pro Pro Leu Pro100 105 110 Ala Ser Val Asn Asn Met Pro Gly Pro Ala Glu Pro Glu Glu SerVal 115 120 125 Asp Ala Leu Lys Leu Cys Pro Arg Glu Asn Phe Val Lys LeuCys Lys 130 135 140 Gln Arg Ala Glu Glu Ile Tyr Pro Ile Lys Glu Arg LysAsp Arg Thr 145 150 155 160 Arg Leu Ala Leu Ile Ile Cys Asn Thr Thr PheAsp His Leu Ser Leu 165 170 175 Arg Lys Gly Ala Asp Leu Asp Val Ala GlyMet Arg Arg Leu Leu Thr 180 185 190 Asp Leu Gly Tyr Ser Val His Ile LysGlu Glu Leu Thr Ala Lys Asp 195 200 205 Met Glu Ser Glu Leu Arg Ala PheAla Ala Arg Pro Glu His Lys Ser 210 215 220 Ser Asp Ser Thr Phe Leu ValPhe Met Ser His Gly Ile Leu Ser Gly 225 230 235 240 Ile Cys Gly Thr LysTyr Ser Ala Glu Gly Asp Pro Asp Val Leu Ala 245 250 255 Tyr Asp Thr IlePhe Gln Ile Phe Asn Asn Arg Asn Cys Leu Ser Leu 260 265 270 Lys Asp LysPro Lys Val Ile Ile Val Gln Ala Cys Arg Gly Glu Asn 275 280 285 Leu GlyGlu Leu Leu Ile Ser Asp Ser Pro Ala Ala Pro Met Asp Ser 290 295 300 ThrSer Gln Met Gly Ser Ser Leu Ser Gln Val Gly Asp Asn Leu Glu 305 310 315320 Asp Asp Ala Ile Tyr Lys Val His Val Glu Lys Asp Phe Ile Ala Phe 325330 335 Cys Ser Ser Thr Pro His His Val Ser Trp Arg Asp Val Asn Lys Gly340 345 350 Ser Leu Phe Ile Thr Gln Leu Ile Thr Cys Phe Gln Lys Tyr SerTrp 355 360 365 Cys Phe His Leu Glu Glu Val Phe Arg Lys Val Gln Gln SerPhe Glu 370 375 380 Lys Pro Asn Val Arg Ala Gln Met Pro Thr Ile Glu ArgLeu Ser Met 385 390 395 400 Thr Arg Cys Phe Tyr Leu Phe Pro Gly His 405410 16 1233 DNA Felis catus 16 ttaatgtcct gggaagaggt agaaacatcttgtcatggat agtcgttcaa tggtgggcat 60 ctgggctcta acatttggtt tttcaaatgactgttgtacc ttccgaaata cttcctccag 120 atgaaagcac cacgaatact tttggaagcacgtgatgagt tgtgtaatga agagagatcc 180 cttgttcacg tctctccaag acacatgatgtggggtcgag gagcagaaag cgatgaagtc 240 cttctccacg tggaccttgt aaatggcgtcgtcctctagg ttgtcaccca cctgtgaaag 300 gctgctaccc atctgtgaag tgctgtccattggggccgct ggagagtcac tgatcaacag 360 ttcccccaaa ttttcacctc tgcaggcctggacgatgatg accttgggct tgtcctttag 420 actaaggcag ttgcggttgt tgaaaatctggaagatggtg tcataagcca atacatctgg 480 gtctccttca gcgctgtact tcgtcccacagattccactc aggatgccat gagacatgaa 540 caccaggaat gtgctgtccg aggacttgtgctctggacgg gcagcaaatg ccctcagctc 600 tgattccatg tccttagcag tgagttcctcttttatgtgc acactgtagc caaggtctgt 660 aagcagcctc ctcatccctg caacgtcaaggtcagccccc ttcctgagag aaagatgatc 720 gaacgtcgta ttgcatatga tgagagccagacgagtacga tcctttctct cctttattgg 780 gtagatctct tcagccctct gtttacacagtttcacgaag ttttcacgag gacaaagctt 840 gagagcatct acagattctt ctggctcagccggcccaggc atgttattca cgctggctgg 900 aagaggagga aacgctactt cagagtccgtggtgttctga gaatttccag attgtgggct 960 tgaggagagc cccagcgtct ctgcaaggtgggtgtcttcc tcacagatgt gacagataaa 1020 gatctggcac gcccgtggcc ctttccgcaggacgctgtcg atcagagctc gggccttgtc 1080 cataacggta gcgttttcac attttactctctccatctcc tcctggttca gcacgttttt 1140 ctcaaagagt tcatccagca agccgttgaccgtccccatg ccgactgagt tgatgaactg 1200 cttcctcttc tccttcagga ccttgtcggccat 1233 17 526 DNA Felis catus CDS (18)..(524) 17 ggcacgagca aaaagccatg gcc gac aag gat ctg aag ggc aag agg aag 50 Met Ala Asp Lys Asp LeuLys Gly Lys Arg Lys 1 5 10 cag ttc atc aac tca gtc ggc atg ggg acg gtcaac ggc ttg ctg gat 98 Gln Phe Ile Asn Ser Val Gly Met Gly Thr Val AsnGly Leu Leu Asp 15 20 25 gaa ctc ttt gag aaa aac gtg ctg aac cag gag gagatg gag aga gta 146 Glu Leu Phe Glu Lys Asn Val Leu Asn Gln Glu Glu MetGlu Arg Val 30 35 40 aaa tgt gaa aac gct acc gtt atg gac aag gcc cga gctctg atc gac 194 Lys Cys Glu Asn Ala Thr Val Met Asp Lys Ala Arg Ala LeuIle Asp 45 50 55 agc gtc ctg cgg aaa ggg cca cgg gcg tgc cag atc ttt atctgt cac 242 Ser Val Leu Arg Lys Gly Pro Arg Ala Cys Gln Ile Phe Ile CysHis 60 65 70 75 atc tgt gag gaa gac acc cac ctt gca gag acg ctg ggg ctctcc tca 290 Ile Cys Glu Glu Asp Thr His Leu Ala Glu Thr Leu Gly Leu SerSer 80 85 90 agc cca caa tct gga aat tct cag aac acc acg gac tct gaa gtagcg 338 Ser Pro Gln Ser Gly Asn Ser Gln Asn Thr Thr Asp Ser Glu Val Ala95 100 105 ttt cct cct ctt cca gcc agc gtg aat aac atg cct ggg ccg gctgag 386 Phe Pro Pro Leu Pro Ala Ser Val Asn Asn Met Pro Gly Pro Ala Glu110 115 120 cca gaa gaa tct gta gat gct ctc aag ctt tgt cct cgt gaa aacttc 434 Pro Glu Glu Ser Val Asp Ala Leu Lys Leu Cys Pro Arg Glu Asn Phe125 130 135 gtg aaa ctg tgt aaa cag agg gct gaa gag atc tac cca ata aaggag 482 Val Lys Leu Cys Lys Gln Arg Ala Glu Glu Ile Tyr Pro Ile Lys Glu140 145 150 155 aga aag gat cgt act cgt ctg gct ctc atc ata tgc aat acgac 526 Arg Lys Asp Arg Thr Arg Leu Ala Leu Ile Ile Cys Asn Thr 160 16518 169 PRT Felis catus 18 Met Ala Asp Lys Asp Leu Lys Gly Lys Arg LysGln Phe Ile Asn Ser 1 5 10 15 Val Gly Met Gly Thr Val Asn Gly Leu LeuAsp Glu Leu Phe Glu Lys 20 25 30 Asn Val Leu Asn Gln Glu Glu Met Glu ArgVal Lys Cys Glu Asn Ala 35 40 45 Thr Val Met Asp Lys Ala Arg Ala Leu IleAsp Ser Val Leu Arg Lys 50 55 60 Gly Pro Arg Ala Cys Gln Ile Phe Ile CysHis Ile Cys Glu Glu Asp 65 70 75 80 Thr His Leu Ala Glu Thr Leu Gly LeuSer Ser Ser Pro Gln Ser Gly 85 90 95 Asn Ser Gln Asn Thr Thr Asp Ser GluVal Ala Phe Pro Pro Leu Pro 100 105 110 Ala Ser Val Asn Asn Met Pro GlyPro Ala Glu Pro Glu Glu Ser Val 115 120 125 Asp Ala Leu Lys Leu Cys ProArg Glu Asn Phe Val Lys Leu Cys Lys 130 135 140 Gln Arg Ala Glu Glu IleTyr Pro Ile Lys Glu Arg Lys Asp Arg Thr 145 150 155 160 Arg Leu Ala LeuIle Ile Cys Asn Thr 165 19 526 DNA Felis catus 19 gtcgtattgc atatgatgagagccagacga gtacgatcct ttctctcctt tattgggtag 60 atctcttcag ccctctgtttacacagtttc acgaagtttt cacgaggaca aagcttgaga 120 gcatctacag attcttctggctcagccggc ccaggcatgt tattcacgct ggctggaaga 180 ggaggaaacg ctacttcagagtccgtggtg ttctgagaat ttccagattg tgggcttgag 240 gagagcccca gcgtctctgcaaggtgggtg tcttcctcac agatgtgaca gataaagatc 300 tggcacgccc gtggccctttccgcaggacg ctgtcgatca gagctcgggc cttgtccata 360 acggtagcgt tttcacattttactctctcc atctcctcct ggttcagcac gtttttctca 420 aagagttcat ccagcaagccgttgaccgtc cccatgccga ctgagttgat gaactgcttc 480 ctcttgccct tcagatccttgtcggccatg gctttttgct cgtgcc 526 20 500 DNA Felis catus CDS (3)..(362)misc_feature (473)..(473) n = unknown at position 473 20 gg gaa ctg ttgatc agt gac tct cca gcg gcc cca atg gac agc act 47 Glu Leu Leu Ile SerAsp Ser Pro Ala Ala Pro Met Asp Ser Thr 1 5 10 15 tca cag atg ggt agcagc ctt tca cag gtg ggt gac aac cta gag gac 95 Ser Gln Met Gly Ser SerLeu Ser Gln Val Gly Asp Asn Leu Glu Asp 20 25 30 gac gcc att tac aag gtccac gtg gag aag gac ttc atc gct ttc tgc 143 Asp Ala Ile Tyr Lys Val HisVal Glu Lys Asp Phe Ile Ala Phe Cys 35 40 45 tcc tcg acc cca cat cat gtgtct tgg aga gac gtg aac aag gga tct 191 Ser Ser Thr Pro His His Val SerTrp Arg Asp Val Asn Lys Gly Ser 50 55 60 ctc ttc att aca caa ctc atc acgtgc ttc caa aag tat tcg tgg tgc 239 Leu Phe Ile Thr Gln Leu Ile Thr CysPhe Gln Lys Tyr Ser Trp Cys 65 70 75 ttt cat ctg gag gaa gta ttt cgg aaggta caa cag tca ttt gaa aaa 287 Phe His Leu Glu Glu Val Phe Arg Lys ValGln Gln Ser Phe Glu Lys 80 85 90 95 cca aat gtt aga gcc cag atg ccc accatt gaa cga cta tcc atg aca 335 Pro Asn Val Arg Ala Gln Met Pro Thr IleGlu Arg Leu Ser Met Thr 100 105 110 aga tac ttc tat ctc ttc cct ggc aattgaaaatagc aatcatgggc 382 Arg Tyr Phe Tyr Leu Phe Pro Gly Asn 115 120agtccagccc ttcttgacca acttggaaaa gtaccttagc tagcacaaca cactcattta 442acgtttggta tctcaataaa aatgaaaaca nctaaaaaaa aaaaaaaaaa aaaaaaaa 500 21120 PRT Felis catus 21 Glu Leu Leu Ile Ser Asp Ser Pro Ala Ala Pro MetAsp Ser Thr Ser 1 5 10 15 Gln Met Gly Ser Ser Leu Ser Gln Val Gly AspAsn Leu Glu Asp Asp 20 25 30 Ala Ile Tyr Lys Val His Val Glu Lys Asp PheIle Ala Phe Cys Ser 35 40 45 Ser Thr Pro His His Val Ser Trp Arg Asp ValAsn Lys Gly Ser Leu 50 55 60 Phe Ile Thr Gln Leu Ile Thr Cys Phe Gln LysTyr Ser Trp Cys Phe 65 70 75 80 His Leu Glu Glu Val Phe Arg Lys Val GlnGln Ser Phe Glu Lys Pro 85 90 95 Asn Val Arg Ala Gln Met Pro Thr Ile GluArg Leu Ser Met Thr Arg 100 105 110 Tyr Phe Tyr Leu Phe Pro Gly Asn 115120 22 500 DNA Felis catus misc_feature (28)..(28) n = unknown atposition 28 22 tttttttttt tttttttttt tttttagntg ttttcatttt tattgagataccaaacgtta 60 aatgagtgtg ttgtgctagc taaggtactt ttccaagttg gtcaagaagggctggactgc 120 ccatgattgc tattttcaat tgccagggaa gagatagaag tatcttgtcatggatagtcg 180 ttcaatggtg ggcatctggg ctctaacatt tggtttttca aatgactgttgtaccttccg 240 aaatacttcc tccagatgaa agcaccacga atacttttgg aagcacgtgatgagttgtgt 300 aatgaagaga gatcccttgt tcacgtctct ccaagacaca tgatgtggggtcgaggagca 360 gaaagcgatg aagtccttct ccacgtggac cttgtaaatg gcgtcgtcctctaggttgtc 420 acccacctgt gaaaggctgc tacccatctg tgaagtgctg tccattggggccgctggaga 480 gtcactgatc aacagttccc 500 23 1230 DNA Felis catus CDS(1)..(1230) 23 atg gcc gac aag gat ctg aag ggc aag agg aag cag ttc atcaac tca 48 Met Ala Asp Lys Asp Leu Lys Gly Lys Arg Lys Gln Phe Ile AsnSer 1 5 10 15 gtc ggc atg ggg acg gtc aac ggc ttg ctg gat gaa ctc tttgag aaa 96 Val Gly Met Gly Thr Val Asn Gly Leu Leu Asp Glu Leu Phe GluLys 20 25 30 aac gtg ctg aac cag gag gag atg gag aga gta aaa tgt gaa aacgct 144 Asn Val Leu Asn Gln Glu Glu Met Glu Arg Val Lys Cys Glu Asn Ala35 40 45 acc gtt atg gac aag gcc cga gct ctg atc gac agc gtc ctg cgg aaa192 Thr Val Met Asp Lys Ala Arg Ala Leu Ile Asp Ser Val Leu Arg Lys 5055 60 ggg cca cgg gcg tgc cag atc ttt atc tgt cac atc tgt gag gaa gac240 Gly Pro Arg Ala Cys Gln Ile Phe Ile Cys His Ile Cys Glu Glu Asp 6570 75 80 acc cac ctt gca gag acg ctg ggg ctc tcc tca agc cca caa tct gga288 Thr His Leu Ala Glu Thr Leu Gly Leu Ser Ser Ser Pro Gln Ser Gly 8590 95 aat tct cag aac acc acg gac tct gaa gta gcg ttt cct cct ctt cca336 Asn Ser Gln Asn Thr Thr Asp Ser Glu Val Ala Phe Pro Pro Leu Pro 100105 110 gcc agc gtg aat aac atg cct ggg ccg gct gag cca gaa gaa tct gta384 Ala Ser Val Asn Asn Met Pro Gly Pro Ala Glu Pro Glu Glu Ser Val 115120 125 gat gct ctc aag ctt tgt cct cgt gaa aac ttc gtg aaa ctg tgt aaa432 Asp Ala Leu Lys Leu Cys Pro Arg Glu Asn Phe Val Lys Leu Cys Lys 130135 140 cag agg gct gaa gag atc tac cca ata aag gag aga aag gat cgt act480 Gln Arg Ala Glu Glu Ile Tyr Pro Ile Lys Glu Arg Lys Asp Arg Thr 145150 155 160 cgt ctg gct ctc atc ata tgc aat acg acg ttc gat cat ctt tctctc 528 Arg Leu Ala Leu Ile Ile Cys Asn Thr Thr Phe Asp His Leu Ser Leu165 170 175 agg aag ggg gct gac ctt gac gtt gca ggg atg agg agg ctg cttaca 576 Arg Lys Gly Ala Asp Leu Asp Val Ala Gly Met Arg Arg Leu Leu Thr180 185 190 gac ctt ggc tac agt gtg cac ata aaa gag gaa ctc act gct aaggac 624 Asp Leu Gly Tyr Ser Val His Ile Lys Glu Glu Leu Thr Ala Lys Asp195 200 205 atg gaa tca gag ctg agg gca ttt gct gcc cgt cca gag cac aagtcc 672 Met Glu Ser Glu Leu Arg Ala Phe Ala Ala Arg Pro Glu His Lys Ser210 215 220 tcg gac agc aca ttc ctg gtg ttc atg tct cat ggc atc ctg agtgga 720 Ser Asp Ser Thr Phe Leu Val Phe Met Ser His Gly Ile Leu Ser Gly225 230 235 240 atc tgt ggg acg aag tac agc gct gaa gga gac cca gat gtattg gct 768 Ile Cys Gly Thr Lys Tyr Ser Ala Glu Gly Asp Pro Asp Val LeuAla 245 250 255 tat gac acc atc ttc cag att ttc aac aac cgc aac tgc cttagt cta 816 Tyr Asp Thr Ile Phe Gln Ile Phe Asn Asn Arg Asn Cys Leu SerLeu 260 265 270 aag gac aag ccc aag gtc atc atc gtc cag gcc tgc aga ggtgaa aat 864 Lys Asp Lys Pro Lys Val Ile Ile Val Gln Ala Cys Arg Gly GluAsn 275 280 285 ttg ggg gaa ctg ttg atc agt gac tct cca gcg gcc cca atggac agc 912 Leu Gly Glu Leu Leu Ile Ser Asp Ser Pro Ala Ala Pro Met AspSer 290 295 300 act tca cag atg ggt agc agc ctt tca cag gtg ggt gac aaccta gag 960 Thr Ser Gln Met Gly Ser Ser Leu Ser Gln Val Gly Asp Asn LeuGlu 305 310 315 320 gac gac gcc att tac aag gtc cac gtg gag aag gac ttcatc gct ttc 1008 Asp Asp Ala Ile Tyr Lys Val His Val Glu Lys Asp Phe IleAla Phe 325 330 335 tgc tcc tcg acc cca cat cat gtg tct tgg aga gac gtgaac aag gga 1056 Cys Ser Ser Thr Pro His His Val Ser Trp Arg Asp Val AsnLys Gly 340 345 350 tct ctc ttc att aca caa ctc atc acg tgc ttc caa aagtat tcg tgg 1104 Ser Leu Phe Ile Thr Gln Leu Ile Thr Cys Phe Gln Lys TyrSer Trp 355 360 365 tgc ttt cat ctg gag gaa gta ttt cgg aag gta caa cagtca ttt gaa 1152 Cys Phe His Leu Glu Glu Val Phe Arg Lys Val Gln Gln SerPhe Glu 370 375 380 aaa cca aat gtt aga gcc cag atg ccc acc att gaa cgacta tcc atg 1200 Lys Pro Asn Val Arg Ala Gln Met Pro Thr Ile Glu Arg LeuSer Met 385 390 395 400 aca aga tac ttc tat ctc ttc cct ggc aat 1230 ThrArg Tyr Phe Tyr Leu Phe Pro Gly Asn 405 410 24 410 PRT Felis catus 24Met Ala Asp Lys Asp Leu Lys Gly Lys Arg Lys Gln Phe Ile Asn Ser 1 5 1015 Val Gly Met Gly Thr Val Asn Gly Leu Leu Asp Glu Leu Phe Glu Lys 20 2530 Asn Val Leu Asn Gln Glu Glu Met Glu Arg Val Lys Cys Glu Asn Ala 35 4045 Thr Val Met Asp Lys Ala Arg Ala Leu Ile Asp Ser Val Leu Arg Lys 50 5560 Gly Pro Arg Ala Cys Gln Ile Phe Ile Cys His Ile Cys Glu Glu Asp 65 7075 80 Thr His Leu Ala Glu Thr Leu Gly Leu Ser Ser Ser Pro Gln Ser Gly 8590 95 Asn Ser Gln Asn Thr Thr Asp Ser Glu Val Ala Phe Pro Pro Leu Pro100 105 110 Ala Ser Val Asn Asn Met Pro Gly Pro Ala Glu Pro Glu Glu SerVal 115 120 125 Asp Ala Leu Lys Leu Cys Pro Arg Glu Asn Phe Val Lys LeuCys Lys 130 135 140 Gln Arg Ala Glu Glu Ile Tyr Pro Ile Lys Glu Arg LysAsp Arg Thr 145 150 155 160 Arg Leu Ala Leu Ile Ile Cys Asn Thr Thr PheAsp His Leu Ser Leu 165 170 175 Arg Lys Gly Ala Asp Leu Asp Val Ala GlyMet Arg Arg Leu Leu Thr 180 185 190 Asp Leu Gly Tyr Ser Val His Ile LysGlu Glu Leu Thr Ala Lys Asp 195 200 205 Met Glu Ser Glu Leu Arg Ala PheAla Ala Arg Pro Glu His Lys Ser 210 215 220 Ser Asp Ser Thr Phe Leu ValPhe Met Ser His Gly Ile Leu Ser Gly 225 230 235 240 Ile Cys Gly Thr LysTyr Ser Ala Glu Gly Asp Pro Asp Val Leu Ala 245 250 255 Tyr Asp Thr IlePhe Gln Ile Phe Asn Asn Arg Asn Cys Leu Ser Leu 260 265 270 Lys Asp LysPro Lys Val Ile Ile Val Gln Ala Cys Arg Gly Glu Asn 275 280 285 Leu GlyGlu Leu Leu Ile Ser Asp Ser Pro Ala Ala Pro Met Asp Ser 290 295 300 ThrSer Gln Met Gly Ser Ser Leu Ser Gln Val Gly Asp Asn Leu Glu 305 310 315320 Asp Asp Ala Ile Tyr Lys Val His Val Glu Lys Asp Phe Ile Ala Phe 325330 335 Cys Ser Ser Thr Pro His His Val Ser Trp Arg Asp Val Asn Lys Gly340 345 350 Ser Leu Phe Ile Thr Gln Leu Ile Thr Cys Phe Gln Lys Tyr SerTrp 355 360 365 Cys Phe His Leu Glu Glu Val Phe Arg Lys Val Gln Gln SerPhe Glu 370 375 380 Lys Pro Asn Val Arg Ala Gln Met Pro Thr Ile Glu ArgLeu Ser Met 385 390 395 400 Thr Arg Tyr Phe Tyr Leu Phe Pro Gly Asn 405410 25 1230 DNA Felis catus 25 attgccaggg aagagataga agtatcttgtcatggatagt cgttcaatgg tgggcatctg 60 ggctctaaca tttggttttt caaatgactgttgtaccttc cgaaatactt cctccagatg 120 aaagcaccac gaatactttt ggaagcacgtgatgagttgt gtaatgaaga gagatccctt 180 gttcacgtct ctccaagaca catgatgtggggtcgaggag cagaaagcga tgaagtcctt 240 ctccacgtgg accttgtaaa tggcgtcgtcctctaggttg tcacccacct gtgaaaggct 300 gctacccatc tgtgaagtgc tgtccattggggccgctgga gagtcactga tcaacagttc 360 ccccaaattt tcacctctgc aggcctggacgatgatgacc ttgggcttgt cctttagact 420 aaggcagttg cggttgttga aaatctggaagatggtgtca taagccaata catctgggtc 480 tccttcagcg ctgtacttcg tcccacagattccactcagg atgccatgag acatgaacac 540 caggaatgtg ctgtccgagg acttgtgctctggacgggca gcaaatgccc tcagctctga 600 ttccatgtcc ttagcagtga gttcctcttttatgtgcaca ctgtagccaa ggtctgtaag 660 cagcctcctc atccctgcaa cgtcaaggtcagcccccttc ctgagagaaa gatgatcgaa 720 cgtcgtattg catatgatga gagccagacgagtacgatcc tttctctcct ttattgggta 780 gatctcttca gccctctgtt tacacagtttcacgaagttt tcacgaggac aaagcttgag 840 agcatctaca gattcttctg gctcagccggcccaggcatg ttattcacgc tggctggaag 900 aggaggaaac gctacttcag agtccgtggtgttctgagaa tttccagatt gtgggcttga 960 ggagagcccc agcgtctctg caaggtgggtgtcttcctca cagatgtgac agataaagat 1020 ctggcacgcc cgtggccctt tccgcaggacgctgtcgatc agagctcggg ccttgtccat 1080 aacggtagcg ttttcacatt ttactctctccatctcctcc tggttcagca cgtttttctc 1140 aaagagttca tccagcaagc cgttgaccgtccccatgccg actgagttga tgaactgctt 1200 cctcttgccc ttcagatcct tgtcggccat1230 26 921 DNA Felis catus CDS (1)..(921) 26 ata tgg gaa ctg gag aaaaac gtt tat gtt gta gag ttg gac tgg cac 48 Ile Trp Glu Leu Glu Lys AsnVal Tyr Val Val Glu Leu Asp Trp His 1 5 10 15 cct gat gcc ccc gga gaaatg gtg gtc ctc acc tgc aat act cct gaa 96 Pro Asp Ala Pro Gly Glu MetVal Val Leu Thr Cys Asn Thr Pro Glu 20 25 30 gaa gat gac atc acc tgg acctct gac cag agc agt gaa gtc cta ggc 144 Glu Asp Asp Ile Thr Trp Thr SerAsp Gln Ser Ser Glu Val Leu Gly 35 40 45 tct ggt aaa act ctg acc atc caagtc aaa gaa ttt gca gat gct ggc 192 Ser Gly Lys Thr Leu Thr Ile Gln ValLys Glu Phe Ala Asp Ala Gly 50 55 60 cag tat acc tgt cat aaa gga ggc gaggtt ctg agc cat tcg ttc ctc 240 Gln Tyr Thr Cys His Lys Gly Gly Glu ValLeu Ser His Ser Phe Leu 65 70 75 80 ctg ata cac aaa aag gaa gat gga atttgg tcc act gat atc tta agg 288 Leu Ile His Lys Lys Glu Asp Gly Ile TrpSer Thr Asp Ile Leu Arg 85 90 95 gaa cag aaa gaa tcc aaa aat aag atc tttcta aaa tgt gag gca aag 336 Glu Gln Lys Glu Ser Lys Asn Lys Ile Phe LeuLys Cys Glu Ala Lys 100 105 110 aat tat tct gga cgt ttc acc tgc tgg tggctg acg gca atc agt acc 384 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp LeuThr Ala Ile Ser Thr 115 120 125 gat ttg aaa ttc act gtc aaa agc agc agaggc tcc tct gac ccc caa 432 Asp Leu Lys Phe Thr Val Lys Ser Ser Arg GlySer Ser Asp Pro Gln 130 135 140 gag gtg act tgt gga gca gcg aca ctc tcagca gag aag gtc aga gtg 480 Glu Val Thr Cys Gly Ala Ala Thr Leu Ser AlaGlu Lys Val Arg Val 145 150 155 160 gac aac agg gat tat aag aag tac acagtg gag tgt cag gag ggc agt 528 Asp Asn Arg Asp Tyr Lys Lys Tyr Thr ValGlu Cys Gln Glu Gly Ser 165 170 175 gcc tgc ccg gct gcc gag gag agc ctaccc att gaa gtc gtg gtg gac 576 Ala Cys Pro Ala Ala Glu Glu Ser Leu ProIle Glu Val Val Val Asp 180 185 190 gct att cac aag ctc aag tac gaa aactac acc agc agc ttc ttc atc 624 Ala Ile His Lys Leu Lys Tyr Glu Asn TyrThr Ser Ser Phe Phe Ile 195 200 205 agg gac atc atc aaa ccg gac cca cccaag aac ctg caa ctg aag cca 672 Arg Asp Ile Ile Lys Pro Asp Pro Pro LysAsn Leu Gln Leu Lys Pro 210 215 220 tta aaa aat tct cgg cat gtg gaa gtgagc tgg gaa tac cct gac acc 720 Leu Lys Asn Ser Arg His Val Glu Val SerTrp Glu Tyr Pro Asp Thr 225 230 235 240 tgg agc acc cca cat tcc tac ttctcc tta aca ttt ggc gta cag gtc 768 Trp Ser Thr Pro His Ser Tyr Phe SerLeu Thr Phe Gly Val Gln Val 245 250 255 cag ggc aag aac aac aga gaa aagaaa gac aga ctc tcc gtg gac aag 816 Gln Gly Lys Asn Asn Arg Glu Lys LysAsp Arg Leu Ser Val Asp Lys 260 265 270 acc tca gcc aag gtc gtg tgc cacaag gat gcc aag atc cgc gtg caa 864 Thr Ser Ala Lys Val Val Cys His LysAsp Ala Lys Ile Arg Val Gln 275 280 285 gcc aga gac cgc tac tat agc tcatcc tgg agc aac tgg gca tcc gtg 912 Ala Arg Asp Arg Tyr Tyr Ser Ser SerTrp Ser Asn Trp Ala Ser Val 290 295 300 tcc tgc agt 921 Ser Cys Ser 30527 307 PRT Felis catus 27 Ile Trp Glu Leu Glu Lys Asn Val Tyr Val ValGlu Leu Asp Trp His 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val LeuThr Cys Asn Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp GlnSer Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val LysGlu Phe Ala Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu ValLeu Ser His Ser Phe Leu 65 70 75 80 Leu Ile His Lys Lys Glu Asp Gly IleTrp Ser Thr Asp Ile Leu Arg 85 90 95 Glu Gln Lys Glu Ser Lys Asn Lys IlePhe Leu Lys Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr CysTrp Trp Leu Thr Ala Ile Ser Thr 115 120 125 Asp Leu Lys Phe Thr Val LysSer Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Glu Val Thr Cys Gly AlaAla Thr Leu Ser Ala Glu Lys Val Arg Val 145 150 155 160 Asp Asn Arg AspTyr Lys Lys Tyr Thr Val Glu Cys Gln Glu Gly Ser 165 170 175 Ala Cys ProAla Ala Glu Glu Ser Leu Pro Ile Glu Val Val Val Asp 180 185 190 Ala IleHis Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile 195 200 205 ArgAsp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro 210 215 220Leu Lys Asn Ser Arg His Val Glu Val Ser Trp Glu Tyr Pro Asp Thr 225 230235 240 Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Gly Val Gln Val245 250 255 Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp Arg Leu Ser Val AspLys 260 265 270 Thr Ser Ala Lys Val Val Cys His Lys Asp Ala Lys Ile ArgVal Gln 275 280 285 Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Asn TrpAla Ser Val 290 295 300 Ser Cys Ser 305 28 921 DNA Felis catus 28actgcaggac acggatgccc agttgctcca ggatgagcta tagtagcggt ctctggcttg 60cacgcggatc ttggcatcct tgtggcacac gaccttggct gaggtcttgt ccacggagag 120tctgtctttc ttttctctgt tgttcttgcc ctggacctgt acgccaaatg ttaaggagaa 180gtaggaatgt ggggtgctcc aggtgtcagg gtattcccag ctcacttcca catgccgaga 240attttttaat ggcttcagtt gcaggttctt gggtgggtcc ggtttgatga tgtccctgat 300gaagaagctg ctggtgtagt tttcgtactt gagcttgtga atagcgtcca ccacgacttc 360aatgggtagg ctctcctcgg cagccgggca ggcactgccc tcctgacact ccactgtgta 420cttcttataa tccctgttgt ccactctgac cttctctgct gagagtgtcg ctgctccaca 480agtcacctct tgggggtcag aggagcctct gctgcttttg acagtgaatt tcaaatcggt 540actgattgcc gtcagccacc agcaggtgaa acgtccagaa taattctttg cctcacattt 600tagaaagatc ttatttttgg attctttctg ttcccttaag atatcagtgg accaaattcc 660atcttccttt ttgtgtatca ggaggaacga atggctcaga acctcgcctc ctttatgaca 720ggtatactgg ccagcatctg caaattcttt gacttggatg gtcagagttt taccagagcc 780taggacttca ctgctctggt cagaggtcca ggtgatgtca tcttcttcag gagtattgca 840ggtgaggacc accatttctc cgggggcatc agggtgccag tccaactcta caacataaac 900gtttttctcc agttcccata t 921 29 987 DNA Felis catus CDS (1)..(987) 29 atgcat cct cag cag ttg gtc atc gcc tgg ttt tcc ctg gtt ttg ctg 48 Met HisPro Gln Gln Leu Val Ile Ala Trp Phe Ser Leu Val Leu Leu 1 5 10 15 gcacct ccc ctc atg gcc ata tgg gaa ctg gag aaa aac gtt tat gtt 96 Ala ProPro Leu Met Ala Ile Trp Glu Leu Glu Lys Asn Val Tyr Val 20 25 30 gta gagttg gac tgg cac cct gat gcc ccc gga gaa atg gtg gtc ctc 144 Val Glu LeuAsp Trp His Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 acc tgc aatact cct gaa gaa gat gac atc acc tgg acc tct gac cag 192 Thr Cys Asn ThrPro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 agc agt gaa gtccta ggc tct ggt aaa act ctg acc atc caa gtc aaa 240 Ser Ser Glu Val LeuGly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 gaa ttt gca gatgct ggc cag tat acc tgt cat aaa gga ggc gag gtt 288 Glu Phe Ala Asp AlaGly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 ctg agc cat tcg ttcctc ctg ata cac aaa aag gaa gat gga att tgg 336 Leu Ser His Ser Phe LeuLeu Ile His Lys Lys Glu Asp Gly Ile Trp 100 105 110 tcc act gat atc ttaagg gaa cag aaa gaa tcc aaa aat aag atc ttt 384 Ser Thr Asp Ile Leu ArgGlu Gln Lys Glu Ser Lys Asn Lys Ile Phe 115 120 125 cta aaa tgt gag gcaaag aat tat tct gga cgt ttc acc tgc tgg tgg 432 Leu Lys Cys Glu Ala LysAsn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 ctg acg gca atc agtacc gat ttg aaa ttc act gtc aaa agc agc aga 480 Leu Thr Ala Ile Ser ThrAsp Leu Lys Phe Thr Val Lys Ser Ser Arg 145 150 155 160 ggc tcc tct gacccc caa ggg gtg act tgt gga gca gcg aca ctc tca 528 Gly Ser Ser Asp ProGln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 gca gag aag gtcaga gtg gac aac agg gat tat aag aag tac aca gtg 576 Ala Glu Lys Val ArgVal Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val 180 185 190 gag tgt cag gagggc agt gcc tgc ccg gct gcc gag gag agc cta ccc 624 Glu Cys Gln Glu GlySer Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro 195 200 205 att gaa gtc gtggtg gac gct att cac aag ctc aag tac gaa aac tac 672 Ile Glu Val Val ValAsp Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr 210 215 220 acc agc agc ttcttc atc agg gac atc atc aaa ccg gac cca ccc aag 720 Thr Ser Ser Phe PheIle Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys 225 230 235 240 aac ctg caactg aag cca tta aaa aat tct cgg cat gtg gaa gtg agc 768 Asn Leu Gln LeuLys Pro Leu Lys Asn Ser Arg His Val Glu Val Ser 245 250 255 tgg gaa taccct gac acc tgg agc acc cca cat tcc tac ttc tcc tta 816 Trp Glu Tyr ProAsp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu 260 265 270 aca ttt ggcgta cag gtc cag ggc aag aac aac aga gaa aag aaa gac 864 Thr Phe Gly ValGln Val Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285 aga ctc tccgtg gac aag acc tca gcc aag gtc gtg tgc cac aag gat 912 Arg Leu Ser ValAsp Lys Thr Ser Ala Lys Val Val Cys His Lys Asp 290 295 300 gcc aag atccgc gtg caa gcc aga gac cgc tac tat agc tca tcc tgg 960 Ala Lys Ile ArgVal Gln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 agc aactgg gca tcc gtg tcc tgc agt 987 Ser Asn Trp Ala Ser Val Ser Cys Ser 32530 329 PRT Felis catus 30 Met His Pro Gln Gln Leu Val Ile Ala Trp PheSer Leu Val Leu Leu 1 5 10 15 Ala Pro Pro Leu Met Ala Ile Trp Glu LeuGlu Lys Asn Val Tyr Val 20 25 30 Val Glu Leu Asp Trp His Pro Asp Ala ProGly Glu Met Val Val Leu 35 40 45 Thr Cys Asn Thr Pro Glu Glu Asp Asp IleThr Trp Thr Ser Asp Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys ThrLeu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Ala Asp Ala Gly Gln Tyr ThrCys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Phe Leu Leu Ile HisLys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Arg Glu GlnLys Glu Ser Lys Asn Lys Ile Phe 115 120 125 Leu Lys Cys Glu Ala Lys AsnTyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Ala Ile Ser ThrAsp Leu Lys Phe Thr Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser AspPro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu LysVal Arg Val Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val 180 185 190 Glu CysGln Glu Gly Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro 195 200 205 IleGlu Val Val Val Asp Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr 210 215 220Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys 225 230235 240 Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg His Val Glu Val Ser245 250 255 Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe SerLeu 260 265 270 Thr Phe Gly Val Gln Val Gln Gly Lys Asn Asn Arg Glu LysLys Asp 275 280 285 Arg Leu Ser Val Asp Lys Thr Ser Ala Lys Val Val CysHis Lys Asp 290 295 300 Ala Lys Ile Arg Val Gln Ala Arg Asp Arg Tyr TyrSer Ser Ser Trp 305 310 315 320 Ser Asn Trp Ala Ser Val Ser Cys Ser 32531 987 DNA Felis catus 31 actgcaggac acggatgccc agttgctcca ggatgagctatagtagcggt ctctggcttg 60 cacgcggatc ttggcatcct tgtggcacac gaccttggctgaggtcttgt ccacggagag 120 tctgtctttc ttttctctgt tgttcttgcc ctggacctgtacgccaaatg ttaaggagaa 180 gtaggaatgt ggggtgctcc aggtgtcagg gtattcccagctcacttcca catgccgaga 240 attttttaat ggcttcagtt gcaggttctt gggtgggtccggtttgatga tgtccctgat 300 gaagaagctg ctggtgtagt tttcgtactt gagcttgtgaatagcgtcca ccacgacttc 360 aatgggtagg ctctcctcgg cagccgggca ggcactgccctcctgacact ccactgtgta 420 cttcttataa tccctgttgt ccactctgac cttctctgctgagagtgtcg ctgctccaca 480 agtcacccct tgggggtcag aggagcctct gctgcttttgacagtgaatt tcaaatcggt 540 actgattgcc gtcagccacc agcaggtgaa acgtccagaataattctttg cctcacattt 600 tagaaagatc ttatttttgg attctttctg ttcccttaagatatcagtgg accaaattcc 660 atcttccttt ttgtgtatca ggaggaacga atggctcagaacctcgcctc ctttatgaca 720 ggtatactgg ccagcatctg caaattcttt gacttggatggtcagagttt taccagagcc 780 taggacttca ctgctctggt cagaggtcca ggtgatgtcatcttcttcag gagtattgca 840 ggtgaggacc accatttctc cgggggcatc agggtgccagtccaactcta caacataaac 900 gtttttctcc agttcccata tggccatgag gggaggtgccagcaaaacca gggaaaacca 960 ggcgatgacc aactgctgag gatgcat 987 32 666 DNAFelis catus CDS (1)..(666) 32 atg tgc ccg ccg cgt ggc ctc ctc ctt gtaacc atc ctg gtc ctg tta 48 Met Cys Pro Pro Arg Gly Leu Leu Leu Val ThrIle Leu Val Leu Leu 1 5 10 15 aac cac ctg gac cac ctc agt ttg gcc aggaac ctc ccc aca ccc aca 96 Asn His Leu Asp His Leu Ser Leu Ala Arg AsnLeu Pro Thr Pro Thr 20 25 30 cca agc cca gga atg ttc cag tgc ctc aac cactcc caa acc ctg ctg 144 Pro Ser Pro Gly Met Phe Gln Cys Leu Asn His SerGln Thr Leu Leu 35 40 45 cga gcc atc agc aac acg ctt cag aag gcc aga caaact cta gaa ttt 192 Arg Ala Ile Ser Asn Thr Leu Gln Lys Ala Arg Gln ThrLeu Glu Phe 50 55 60 tac tcc tgc act tcc gaa gag att gat cat gaa gat atcaca aaa gat 240 Tyr Ser Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile ThrLys Asp 65 70 75 80 aaa acc agc aca gtg gag gcc tgc tta cca ctg gaa ttaacc atg aat 288 Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu ThrMet Asn 85 90 95 gag agt tgc ctg gct tcc aga gag atc tct ctg ata act aatggg agt 336 Glu Ser Cys Leu Ala Ser Arg Glu Ile Ser Leu Ile Thr Asn GlySer 100 105 110 tgc ctg gcc tcc aga aag acc tct ttt atg acg acc ctg tgcctt agc 384 Cys Leu Ala Ser Arg Lys Thr Ser Phe Met Thr Thr Leu Cys LeuSer 115 120 125 agt atc tat gag gac ttg aag atg tac cag gtg gag ttc aaggcc atg 432 Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys AlaMet 130 135 140 aat gca aag ctg tta atg gat cct aaa agg cag atc ttt ctggat caa 480 Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu AspGln 145 150 155 160 aac atg ctg aca gct att gat gag ctg tta cag gcc ctgaat gtc aac 528 Asn Met Leu Thr Ala Ile Asp Glu Leu Leu Gln Ala Leu AsnVal Asn 165 170 175 agt gtg act gtg cca cag aac tcc tcc ctg gaa gaa ccggat ttt tat 576 Ser Val Thr Val Pro Gln Asn Ser Ser Leu Glu Glu Pro AspPhe Tyr 180 185 190 aaa act aaa atc aag ctc tgc ata ctt ctt cat gct ttcaga att cgt 624 Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe ArgIle Arg 195 200 205 gca gtg acc atc aat aga atg atg agc tat ctg aat gcttcc 666 Ala Val Thr Ile Asn Arg Met Met Ser Tyr Leu Asn Ala Ser 210 215220 33 222 PRT Felis catus 33 Met Cys Pro Pro Arg Gly Leu Leu Leu ValThr Ile Leu Val Leu Leu 1 5 10 15 Asn His Leu Asp His Leu Ser Leu AlaArg Asn Leu Pro Thr Pro Thr 20 25 30 Pro Ser Pro Gly Met Phe Gln Cys LeuAsn His Ser Gln Thr Leu Leu 35 40 45 Arg Ala Ile Ser Asn Thr Leu Gln LysAla Arg Gln Thr Leu Glu Phe 50 55 60 Tyr Ser Cys Thr Ser Glu Glu Ile AspHis Glu Asp Ile Thr Lys Asp 65 70 75 80 Lys Thr Ser Thr Val Glu Ala CysLeu Pro Leu Glu Leu Thr Met Asn 85 90 95 Glu Ser Cys Leu Ala Ser Arg GluIle Ser Leu Ile Thr Asn Gly Ser 100 105 110 Cys Leu Ala Ser Arg Lys ThrSer Phe Met Thr Thr Leu Cys Leu Ser 115 120 125 Ser Ile Tyr Glu Asp LeuLys Met Tyr Gln Val Glu Phe Lys Ala Met 130 135 140 Asn Ala Lys Leu LeuMet Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln 145 150 155 160 Asn Met LeuThr Ala Ile Asp Glu Leu Leu Gln Ala Leu Asn Val Asn 165 170 175 Ser ValThr Val Pro Gln Asn Ser Ser Leu Glu Glu Pro Asp Phe Tyr 180 185 190 LysThr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg 195 200 205Ala Val Thr Ile Asn Arg Met Met Ser Tyr Leu Asn Ala Ser 210 215 220 34666 DNA Felis catus 34 ggaagcattc agatagctca tcattctatt gatggtcactgcacgaattc tgaaagcatg 60 aagaagtatg cagagcttga ttttagtttt ataaaaatccggttcttcca gggaggagtt 120 ctgtggcaca gtcacactgt tgacattcag ggcctgtaacagctcatcaa tagctgtcag 180 catgttttga tccagaaaga tctgcctttt aggatccattaacagctttg cattcatggc 240 cttgaactcc acctggtaca tcttcaagtc ctcatagatactgctaaggc acagggtcgt 300 cataaaagag gtctttctgg aggccaggca actcccattagttatcagag agatctctct 360 ggaagccagg caactctcat tcatggttaa ttccagtggtaagcaggcct ccactgtgct 420 ggttttatct tttgtgatat cttcatgatc aatctcttcggaagtgcagg agtaaaattc 480 tagagtttgt ctggccttct gaagcgtgtt gctgatggctcgcagcaggg tttgggagtg 540 gttgaggcac tggaacattc ctgggcttgg tgtgggtgtggggaggttcc tggccaaact 600 gaggtggtcc aggtggttta acaggaccag gatggttacaaggaggaggc cacgcggcgg 660 gcacat 666 35 591 DNA Felis catus CDS(1)..(591) 35 agg aac ctc ccc aca ccc aca cca agc cca gga atg ttc cagtgc ctc 48 Arg Asn Leu Pro Thr Pro Thr Pro Ser Pro Gly Met Phe Gln CysLeu 1 5 10 15 aac cac tcc caa acc ctg ctg cga gcc atc agc aac acg cttcag aag 96 Asn His Ser Gln Thr Leu Leu Arg Ala Ile Ser Asn Thr Leu GlnLys 20 25 30 gcc aga caa act cta gaa ttt tac tcc tgc act tcc gaa gag attgat 144 Ala Arg Gln Thr Leu Glu Phe Tyr Ser Cys Thr Ser Glu Glu Ile Asp35 40 45 cat gaa gat atc aca aaa gat aaa acc agc aca gtg gag gcc tgc tta192 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 5055 60 cca ctg gaa tta acc atg aat gag agt tgc ctg gct tcc aga gag atc240 Pro Leu Glu Leu Thr Met Asn Glu Ser Cys Leu Ala Ser Arg Glu Ile 6570 75 80 tct ctg ata act aat ggg agt tgc ctg gcc tcc aga aag acc tct ttt288 Ser Leu Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 8590 95 atg acg acc ctg tgc ctt agc agt atc tat gag gac ttg aag atg tac336 Met Thr Thr Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100105 110 cag gtg gag ttc aag gcc atg aat gca aag ctg tta atg gat cct aaa384 Gln Val Glu Phe Lys Ala Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115120 125 agg cag atc ttt ctg gat caa aac atg ctg aca gct att gat gag ctg432 Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Thr Ala Ile Asp Glu Leu 130135 140 tta cag gcc ctg aat gtc aac agt gtg act gtg cca cag aac tcc tcc480 Leu Gln Ala Leu Asn Val Asn Ser Val Thr Val Pro Gln Asn Ser Ser 145150 155 160 ttg gaa gaa ccg gat ttt tat aaa act aaa atc aag ctc tgc atactt 528 Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu165 170 175 ctt cat gct ttc aga att cgt gca gtg acc atc aat aga atg atgagc 576 Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asn Arg Met Met Ser180 185 190 tat ctg aat gct tcc 591 Tyr Leu Asn Ala Ser 195 36 197 PRTFelis catus 36 Arg Asn Leu Pro Thr Pro Thr Pro Ser Pro Gly Met Phe GlnCys Leu 1 5 10 15 Asn His Ser Gln Thr Leu Leu Arg Ala Ile Ser Asn ThrLeu Gln Lys 20 25 30 Ala Arg Gln Thr Leu Glu Phe Tyr Ser Cys Thr Ser GluGlu Ile Asp 35 40 45 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val GluAla Cys Leu 50 55 60 Pro Leu Glu Leu Thr Met Asn Glu Ser Cys Leu Ala SerArg Glu Ile 65 70 75 80 Ser Leu Ile Thr Asn Gly Ser Cys Leu Ala Ser ArgLys Thr Ser Phe 85 90 95 Met Thr Thr Leu Cys Leu Ser Ser Ile Tyr Glu AspLeu Lys Met Tyr 100 105 110 Gln Val Glu Phe Lys Ala Met Asn Ala Lys LeuLeu Met Asp Pro Lys 115 120 125 Arg Gln Ile Phe Leu Asp Gln Asn Met LeuThr Ala Ile Asp Glu Leu 130 135 140 Leu Gln Ala Leu Asn Val Asn Ser ValThr Val Pro Gln Asn Ser Ser 145 150 155 160 Leu Glu Glu Pro Asp Phe TyrLys Thr Lys Ile Lys Leu Cys Ile Leu 165 170 175 Leu His Ala Phe Arg IleArg Ala Val Thr Ile Asn Arg Met Met Ser 180 185 190 Tyr Leu Asn Ala Ser195 37 591 DNA Felis catus 37 ggaagcattc agatagctca tcattctattgatggtcact gcacgaattc tgaaagcatg 60 aagaagtatg cagagcttga ttttagttttataaaaatcc ggttcttcca aggaggagtt 120 ctgtggcaca gtcacactgt tgacattcagggcctgtaac agctcatcaa tagctgtcag 180 catgttttga tccagaaaga tctgccttttaggatccatt aacagctttg cattcatggc 240 cttgaactcc acctggtaca tcttcaagtcctcatagata ctgctaaggc acagggtcgt 300 cataaaagag gtctttctgg aggccaggcaactcccatta gttatcagag agatctctct 360 ggaagccagg caactctcat tcatggttaattccagtggt aagcaggcct ccactgtgct 420 ggttttatct tttgtgatat cttcatgatcaatctcttcg gaagtgcagg agtaaaattc 480 tagagtttgt ctggccttct gaagcgtgttgctgatggct cgcagcaggg tttgggagtg 540 gttgaggcac tggaacattc ctgggcttggtgtgggtgtg gggaggttcc t 591 38 1599 DNA Felis catus CDS (1)..(1599) 38atg cat cct cag cag ttg gtc atc gcc tgg ctt tcc ctg gtt ttg ctg 48 MetHis Pro Gln Gln Leu Val Ile Ala Trp Leu Ser Leu Val Leu Leu 1 5 10 15gca cct ccc ctc atg gcc ata tgg gaa ctg gag aaa aac gtt tat gtt 96 AlaPro Pro Leu Met Ala Ile Trp Glu Leu Glu Lys Asn Val Tyr Val 20 25 30 gtagag ttg gac tgg cac cct gat gcc ccc gga gaa atg gtg gtc ctc 144 Val GluLeu Asp Trp His Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 acc tgcaat act cct gaa gaa gat gac atc acc tgg acc tct gac cag 192 Thr Cys AsnThr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 agc agt gaagtc cta ggc tct ggt aaa act ctg acc atc caa gtc aaa 240 Ser Ser Glu ValLeu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 gaa ttt gcagat gct ggc cag tat acc tgt cat aaa gga ggc gag gtt 288 Glu Phe Ala AspAla Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 ctg agc cat tcgttc ctc ctg ata cac aaa aag gaa gat gga att tgg 336 Leu Ser His Ser PheLeu Leu Ile His Lys Lys Glu Asp Gly Ile Trp 100 105 110 tcc act gat atctta agg gaa cag aaa gaa tcc aaa aat aag atc ttt 384 Ser Thr Asp Ile LeuArg Glu Gln Lys Glu Ser Lys Asn Lys Ile Phe 115 120 125 cta aaa tgt gaggca aag aat tat tct gga cgt ttc acc tgc tgg tgg 432 Leu Lys Cys Glu AlaLys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 ctg acg gca atcagt acc gat ttg aaa ttc act gtc aaa agc agc aga 480 Leu Thr Ala Ile SerThr Asp Leu Lys Phe Thr Val Lys Ser Ser Arg 145 150 155 160 ggc tcc tctgac ccc caa gag gtg act tgt gga gca gcg aca ctc tca 528 Gly Ser Ser AspPro Gln Glu Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 gca gag aaggtc aga gtg gac aac agg gat tat aag aag tac aca gtg 576 Ala Glu Lys ValArg Val Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val 180 185 190 gag tgt caggag ggc agt gcc tgc ccg gct gcc gag gag agc cta ccc 624 Glu Cys Gln GluGly Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro 195 200 205 att gaa gtcgtg gtg gac gct att cac aag ctc aag tac gaa aac tac 672 Ile Glu Val ValVal Asp Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr 210 215 220 acc agc agcttc ttc atc agg gac atc atc aaa ccg gac cca ccc aag 720 Thr Ser Ser PhePhe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys 225 230 235 240 aac ctgcaa ctg aag cca tta aaa aat tct cgg cat gtg gaa gtg agc 768 Asn Leu GlnLeu Lys Pro Leu Lys Asn Ser Arg His Val Glu Val Ser 245 250 255 tgg gaatac cct gac acc tgg agc acc cca cat tcc tac ttc tcc tta 816 Trp Glu TyrPro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu 260 265 270 aca tttggc gta cag gtc cag ggc aag aac aac aga gaa aag aaa gac 864 Thr Phe GlyVal Gln Val Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285 aga ctctcc gtg gac aag acc tca gcc aag gtc gtg tgc cac aag gat 912 Arg Leu SerVal Asp Lys Thr Ser Ala Lys Val Val Cys His Lys Asp 290 295 300 gcc aagatc cgc gtg caa gcc aga gac cgc tac tat agc tca tcc tgg 960 Ala Lys IleArg Val Gln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 agcaac tgg gca tcc gtg tcc tgc agt ggt ggc ggt ggc ggc gga tct 1008 Ser AsnTrp Ala Ser Val Ser Cys Ser Gly Gly Gly Gly Gly Gly Ser 325 330 335 agaaac ttg cca acc cct act cca tcc ccg ggg atg ttc cag tgc ctc 1056 Arg AsnLeu Pro Thr Pro Thr Pro Ser Pro Gly Met Phe Gln Cys Leu 340 345 350 aaccac tcc caa acc ctg ctg cga gcc atc agc aac acg ctt cag aag 1104 Asn HisSer Gln Thr Leu Leu Arg Ala Ile Ser Asn Thr Leu Gln Lys 355 360 365 gccaga caa act cta gaa ttt tac tcc tgc act tcc gaa gag att gat 1152 Ala ArgGln Thr Leu Glu Phe Tyr Ser Cys Thr Ser Glu Glu Ile Asp 370 375 380 catgaa gat atc aca aaa gat aaa acc agc aca gtg gag gcc tgc tta 1200 His GluAsp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 385 390 395 400cca ctg gaa tta acc atg aat gag agt tgc ctg gct tcc aga gag atc 1248 ProLeu Glu Leu Thr Met Asn Glu Ser Cys Leu Ala Ser Arg Glu Ile 405 410 415tct ctg ata act aat ggg agt tgc ctg gcc tcc aga aag acc tct ttt 1296 SerLeu Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 420 425 430atg acg acc ctg tgc ctt agc agt atc tat gag gac ttg aag atg tac 1344 MetThr Thr Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 435 440 445cag gtg gag ttc aag gcc atg aat gca aag ctg tta atg gat cct aaa 1392 GlnVal Glu Phe Lys Ala Met Asn Ala Lys Leu Leu Met Asp Pro Lys 450 455 460agg cag atc ttt ctg gat caa aac atg ctg aca gct att gat gag ctg 1440 ArgGln Ile Phe Leu Asp Gln Asn Met Leu Thr Ala Ile Asp Glu Leu 465 470 475480 tta cag gcc ctg aat gtc aac agt gtg act gtg cca cag aac tcc tcc 1488Leu Gln Ala Leu Asn Val Asn Ser Val Thr Val Pro Gln Asn Ser Ser 485 490495 ttg gaa gaa ccg gat ttt tat aaa act aaa atc aag ctc tgc ata ctt 1536Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 500 505510 ctt cat gct ttc aga att cgt gca gtg acc atc aat aga atg atg agc 1584Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asn Arg Met Met Ser 515 520525 tat ctg aat gct tcc 1599 Tyr Leu Asn Ala Ser 530 39 533 PRT Feliscatus 39 Met His Pro Gln Gln Leu Val Ile Ala Trp Leu Ser Leu Val Leu Leu1 5 10 15 Ala Pro Pro Leu Met Ala Ile Trp Glu Leu Glu Lys Asn Val TyrVal 20 25 30 Val Glu Leu Asp Trp His Pro Asp Ala Pro Gly Glu Met Val ValLeu 35 40 45 Thr Cys Asn Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser AspGln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln ValLys 65 70 75 80 Glu Phe Ala Asp Ala Gly Gln Tyr Thr Cys His Lys Gly GlyGlu Val 85 90 95 Leu Ser His Ser Phe Leu Leu Ile His Lys Lys Glu Asp GlyIle Trp 100 105 110 Ser Thr Asp Ile Leu Arg Glu Gln Lys Glu Ser Lys AsnLys Ile Phe 115 120 125 Leu Lys Cys Glu Ala Lys Asn Tyr Ser Gly Arg PheThr Cys Trp Trp 130 135 140 Leu Thr Ala Ile Ser Thr Asp Leu Lys Phe ThrVal Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Glu Val ThrCys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Lys Val Arg Val Asp AsnArg Asp Tyr Lys Lys Tyr Thr Val 180 185 190 Glu Cys Gln Glu Gly Ser AlaCys Pro Ala Ala Glu Glu Ser Leu Pro 195 200 205 Ile Glu Val Val Val AspAla Ile His Lys Leu Lys Tyr Glu Asn Tyr 210 215 220 Thr Ser Ser Phe PheIle Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys 225 230 235 240 Asn Leu GlnLeu Lys Pro Leu Lys Asn Ser Arg His Val Glu Val Ser 245 250 255 Trp GluTyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu 260 265 270 ThrPhe Gly Val Gln Val Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285Arg Leu Ser Val Asp Lys Thr Ser Ala Lys Val Val Cys His Lys Asp 290 295300 Ala Lys Ile Arg Val Gln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305310 315 320 Ser Asn Trp Ala Ser Val Ser Cys Ser Gly Gly Gly Gly Gly GlySer 325 330 335 Arg Asn Leu Pro Thr Pro Thr Pro Ser Pro Gly Met Phe GlnCys Leu 340 345 350 Asn His Ser Gln Thr Leu Leu Arg Ala Ile Ser Asn ThrLeu Gln Lys 355 360 365 Ala Arg Gln Thr Leu Glu Phe Tyr Ser Cys Thr SerGlu Glu Ile Asp 370 375 380 His Glu Asp Ile Thr Lys Asp Lys Thr Ser ThrVal Glu Ala Cys Leu 385 390 395 400 Pro Leu Glu Leu Thr Met Asn Glu SerCys Leu Ala Ser Arg Glu Ile 405 410 415 Ser Leu Ile Thr Asn Gly Ser CysLeu Ala Ser Arg Lys Thr Ser Phe 420 425 430 Met Thr Thr Leu Cys Leu SerSer Ile Tyr Glu Asp Leu Lys Met Tyr 435 440 445 Gln Val Glu Phe Lys AlaMet Asn Ala Lys Leu Leu Met Asp Pro Lys 450 455 460 Arg Gln Ile Phe LeuAsp Gln Asn Met Leu Thr Ala Ile Asp Glu Leu 465 470 475 480 Leu Gln AlaLeu Asn Val Asn Ser Val Thr Val Pro Gln Asn Ser Ser 485 490 495 Leu GluGlu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 500 505 510 LeuHis Ala Phe Arg Ile Arg Ala Val Thr Ile Asn Arg Met Met Ser 515 520 525Tyr Leu Asn Ala Ser 530 40 1599 DNA Felis catus 40 ggaagcattc agatagctcatcattctatt gatggtcact gcacgaattc tgaaagcatg 60 aagaagtatg cagagcttgattttagtttt ataaaaatcc ggttcttcca aggaggagtt 120 ctgtggcaca gtcacactgttgacattcag ggcctgtaac agctcatcaa tagctgtcag 180 catgttttga tccagaaagatctgcctttt aggatccatt aacagctttg cattcatggc 240 cttgaactcc acctggtacatcttcaagtc ctcatagata ctgctaaggc acagggtcgt 300 cataaaagag gtctttctggaggccaggca actcccatta gttatcagag agatctctct 360 ggaagccagg caactctcattcatggttaa ttccagtggt aagcaggcct ccactgtgct 420 ggttttatct tttgtgatatcttcatgatc aatctcttcg gaagtgcagg agtaaaattc 480 tagagtttgt ctggccttctgaagcgtgtt gctgatggct cgcagcaggg tttgggagtg 540 gttgaggcac tggaacatccccggggatgg agtaggggtt ggcaagtttc tagatccgcc 600 gccaccgcca ccactgcaggacacggatgc ccagttgctc caggatgagc tatagtagcg 660 gtctctggct tgcacgcggatcttggcatc cttgtggcac acgaccttgg ctgaggtctt 720 gtccacggag agtctgtctttcttttctct gttgttcttg ccctggacct gtacgccaaa 780 tgttaaggag aagtaggaatgtggggtgct ccaggtgtca gggtattccc agctcacttc 840 cacatgccga gaattttttaatggcttcag ttgcaggttc ttgggtgggt ccggtttgat 900 gatgtccctg atgaagaagctgctggtgta gttttcgtac ttgagcttgt gaatagcgtc 960 caccacgact tcaatgggtaggctctcctc ggcagccggg caggcactgc cctcctgaca 1020 ctccactgtg tacttcttataatccctgtt gtccactctg accttctctg ctgagagtgt 1080 cgctgctcca caagtcacctcttgggggtc agaggagcct ctgctgcttt tgacagtgaa 1140 tttcaaatcg gtactgattgccgtcagcca ccagcaggtg aaacgtccag aataattctt 1200 tgcctcacat tttagaaagatcttattttt ggattctttc tgttccctta agatatcagt 1260 ggaccaaatt ccatcttcctttttgtgtat caggaggaac gaatggctca gaacctcgcc 1320 tcctttatga caggtatactggccagcatc tgcaaattct ttgacttgga tggtcagagt 1380 tttaccagag cctaggacttcactgctctg gtcagaggtc caggtgatgt catcttcttc 1440 aggagtattg caggtgaggaccaccatttc tccgggggca tcagggtgcc agtccaactc 1500 tacaacataa acgtttttctccagttccca tatggccatg aggggaggtg ccagcaaaac 1560 cagggaaagc caggcgatgaccaactgctg aggatgcat 1599 41 576 DNA Felis catus 41 aattcttgttttgaacagtg aacattatgg acttatcccc attttcatcc ttttttttca 60 aaatgagtttgaaaagatct ttctcttttt cacaagctag aaagtacccc ttgtacaatg 120 aagactcaaattgtatctta tcatcatgtc ctggaacact tctctgaaag aatatgatgt 180 catttccttcatcattgata ctctcaggag gactcatttc cttaaaggaa ataattttgt 240 tctcacaggagagagtagac atggtcttat aattcacaga gatggttact gccagacctc 300 tagtgaggctatctttatac atatatatga taaattcagt ccggggtgca ttatctgtac 360 agtcagaatcaggcatatcc tcaaacacag gttgatctcc ctggttaatg aagagaactt 420 ggtcgttcaagtttcgtaag attgagagtt tatgttcaag cttgccaaag taatctgttt 480 ccaggttttcatcactgtca gctacaaagt aaagtgtatt gtcaataaat ttcattccca 540 caaagttgatgcaatcatct actggtatag cagtca 576 42 0 DNA Felis catus 42 000 43 1533 DNAFelis catus CDS (1)..(1533) 43 ata tgg gaa ctg gag aaa aac gtt tat gttgta gag ttg gac tgg cac 48 Ile Trp Glu Leu Glu Lys Asn Val Tyr Val ValGlu Leu Asp Trp His 1 5 10 15 cct gat gcc ccc gga gaa atg gtg gtc ctcacc tgc aat act cct gaa 96 Pro Asp Ala Pro Gly Glu Met Val Val Leu ThrCys Asn Thr Pro Glu 20 25 30 gaa gat gac atc acc tgg acc tct gac cag agcagt gaa gtc cta ggc 144 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Ser SerGlu Val Leu Gly 35 40 45 tct ggt aaa act ctg acc atc caa gtc aaa gaa tttgca gat gct ggc 192 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe AlaAsp Ala Gly 50 55 60 cag tat acc tgt cat aaa gga ggc gag gtt ctg agc cattcg ttc ctc 240 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His SerPhe Leu 65 70 75 80 ctg ata cac aaa aag gaa gat gga att tgg tcc act gatatc tta agg 288 Leu Ile His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp IleLeu Arg 85 90 95 gaa cag aaa gaa tcc aaa aat aag atc ttt cta aaa tgt gaggca aag 336 Glu Gln Lys Glu Ser Lys Asn Lys Ile Phe Leu Lys Cys Glu AlaLys 100 105 110 aat tat tct gga cgt ttc acc tgc tgg tgg ctg acg gca atcagt acc 384 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Ala Ile SerThr 115 120 125 gat ttg aaa ttc act gtc aaa agc agc aga ggc tcc tct gacccc caa 432 Asp Leu Lys Phe Thr Val Lys Ser Ser Arg Gly Ser Ser Asp ProGln 130 135 140 gag gtg act tgt gga gca gcg aca ctc tca gca gag aag gtcaga gtg 480 Glu Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Lys Val ArgVal 145 150 155 160 gac aac agg gat tat aag aag tac aca gtg gag tgt caggag ggc agt 528 Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val Glu Cys Gln GluGly Ser 165 170 175 gcc tgc ccg gct gcc gag gag agc cta ccc att gaa gtcgtg gtg gac 576 Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val ValVal Asp 180 185 190 gct att cac aag ctc aag tac gaa aac tac acc agc agcttc ttc atc 624 Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser PhePhe Ile 195 200 205 agg gac atc atc aaa ccg gac cca ccc aag aac ctg caactg aag cca 672 Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln LeuLys Pro 210 215 220 tta aaa aat tct cgg cat gtg gaa gtg agc tgg gaa taccct gac acc 720 Leu Lys Asn Ser Arg His Val Glu Val Ser Trp Glu Tyr ProAsp Thr 225 230 235 240 tgg agc acc cca cat tcc tac ttc tcc tta aca tttggc gta cag gtc 768 Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe GlyVal Gln Val 245 250 255 cag ggc aag aac aac aga gaa aag aaa gac aga ctctcc gtg gac aag 816 Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp Arg Leu SerVal Asp Lys 260 265 270 acc tca gcc aag gtc gtg tgc cac aag gat gcc aagatc cgc gtg caa 864 Thr Ser Ala Lys Val Val Cys His Lys Asp Ala Lys IleArg Val Gln 275 280 285 gcc aga gac cgc tac tat agc tca tcc tgg agc aactgg gca tcc gtg 912 Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Asn TrpAla Ser Val 290 295 300 tcc tgc agt ggt ggc ggt ggc ggc gga tct aga aacttg cca acc cct 960 Ser Cys Ser Gly Gly Gly Gly Gly Gly Ser Arg Asn LeuPro Thr Pro 305 310 315 320 act cca tcc ccg ggg atg ttc cag tgc ctc aaccac tcc caa acc ctg 1008 Thr Pro Ser Pro Gly Met Phe Gln Cys Leu Asn HisSer Gln Thr Leu 325 330 335 ctg cga gcc atc agc aac acg ctt cag aag gccaga caa act cta gaa 1056 Leu Arg Ala Ile Ser Asn Thr Leu Gln Lys Ala ArgGln Thr Leu Glu 340 345 350 ttt tac tcc tgc act tcc gaa gag att gat catgaa gat atc aca aaa 1104 Phe Tyr Ser Cys Thr Ser Glu Glu Ile Asp His GluAsp Ile Thr Lys 355 360 365 gat aaa acc agc aca gtg gag gcc tgc tta ccactg gaa tta acc atg 1152 Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro LeuGlu Leu Thr Met 370 375 380 aat gag agt tgc ctg gct tcc aga gag atc tctctg ata act aat ggg 1200 Asn Glu Ser Cys Leu Ala Ser Arg Glu Ile Ser LeuIle Thr Asn Gly 385 390 395 400 agt tgc ctg gcc tcc aga aag acc tct tttatg acg acc ctg tgc ctt 1248 Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe MetThr Thr Leu Cys Leu 405 410 415 agc agt atc tat gag gac ttg aag atg taccag gtg gag ttc aag gcc 1296 Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr GlnVal Glu Phe Lys Ala 420 425 430 atg aat gca aag ctg tta atg gat cct aaaagg cag atc ttt ctg gat 1344 Met Asn Ala Lys Leu Leu Met Asp Pro Lys ArgGln Ile Phe Leu Asp 435 440 445 caa aac atg ctg aca gct att gat gag ctgtta cag gcc ctg aat gtc 1392 Gln Asn Met Leu Thr Ala Ile Asp Glu Leu LeuGln Ala Leu Asn Val 450 455 460 aac agt gtg act gtg cca cag aac tcc tccttg gaa gaa ccg gat ttt 1440 Asn Ser Val Thr Val Pro Gln Asn Ser Ser LeuGlu Glu Pro Asp Phe 465 470 475 480 tat aaa act aaa atc aag ctc tgc atactt ctt cat gct ttc aga att 1488 Tyr Lys Thr Lys Ile Lys Leu Cys Ile LeuLeu His Ala Phe Arg Ile 485 490 495 cgt gca gtg acc atc aat aga atg atgagc tat ctg aat gct tcc 1533 Arg Ala Val Thr Ile Asn Arg Met Met Ser TyrLeu Asn Ala Ser 500 505 510 44 511 PRT Felis catus 44 Ile Trp Glu LeuGlu Lys Asn Val Tyr Val Val Glu Leu Asp Trp His 1 5 10 15 Pro Asp AlaPro Gly Glu Met Val Val Leu Thr Cys Asn Thr Pro Glu 20 25 30 Glu Asp AspIle Thr Trp Thr Ser Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly LysThr Leu Thr Ile Gln Val Lys Glu Phe Ala Asp Ala Gly 50 55 60 Gln Tyr ThrCys His Lys Gly Gly Glu Val Leu Ser His Ser Phe Leu 65 70 75 80 Leu IleHis Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Arg 85 90 95 Glu GlnLys Glu Ser Lys Asn Lys Ile Phe Leu Lys Cys Glu Ala Lys 100 105 110 AsnTyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Ala Ile Ser Thr 115 120 125Asp Leu Lys Phe Thr Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135140 Glu Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Lys Val Arg Val 145150 155 160 Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val Glu Cys Gln Glu GlySer 165 170 175 Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val ValVal Asp 180 185 190 Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser SerPhe Phe Ile 195 200 205 Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn LeuGln Leu Lys Pro 210 215 220 Leu Lys Asn Ser Arg His Val Glu Val Ser TrpGlu Tyr Pro Asp Thr 225 230 235 240 Trp Ser Thr Pro His Ser Tyr Phe SerLeu Thr Phe Gly Val Gln Val 245 250 255 Gln Gly Lys Asn Asn Arg Glu LysLys Asp Arg Leu Ser Val Asp Lys 260 265 270 Thr Ser Ala Lys Val Val CysHis Lys Asp Ala Lys Ile Arg Val Gln 275 280 285 Ala Arg Asp Arg Tyr TyrSer Ser Ser Trp Ser Asn Trp Ala Ser Val 290 295 300 Ser Cys Ser Gly GlyGly Gly Gly Gly Ser Arg Asn Leu Pro Thr Pro 305 310 315 320 Thr Pro SerPro Gly Met Phe Gln Cys Leu Asn His Ser Gln Thr Leu 325 330 335 Leu ArgAla Ile Ser Asn Thr Leu Gln Lys Ala Arg Gln Thr Leu Glu 340 345 350 PheTyr Ser Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys 355 360 365Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Met 370 375380 Asn Glu Ser Cys Leu Ala Ser Arg Glu Ile Ser Leu Ile Thr Asn Gly 385390 395 400 Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met Thr Thr Leu CysLeu 405 410 415 Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu PheLys Ala 420 425 430 Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln IlePhe Leu Asp 435 440 445 Gln Asn Met Leu Thr Ala Ile Asp Glu Leu Leu GlnAla Leu Asn Val 450 455 460 Asn Ser Val Thr Val Pro Gln Asn Ser Ser LeuGlu Glu Pro Asp Phe 465 470 475 480 Tyr Lys Thr Lys Ile Lys Leu Cys IleLeu Leu His Ala Phe Arg Ile 485 490 495 Arg Ala Val Thr Ile Asn Arg MetMet Ser Tyr Leu Asn Ala Ser 500 505 510 45 1533 DNA Felis catus 45ggaagcattc agatagctca tcattctatt gatggtcact gcacgaattc tgaaagcatg 60aagaagtatg cagagcttga ttttagtttt ataaaaatcc ggttcttcca aggaggagtt 120ctgtggcaca gtcacactgt tgacattcag ggcctgtaac agctcatcaa tagctgtcag 180catgttttga tccagaaaga tctgcctttt aggatccatt aacagctttg cattcatggc 240cttgaactcc acctggtaca tcttcaagtc ctcatagata ctgctaaggc acagggtcgt 300cataaaagag gtctttctgg aggccaggca actcccatta gttatcagag agatctctct 360ggaagccagg caactctcat tcatggttaa ttccagtggt aagcaggcct ccactgtgct 420ggttttatct tttgtgatat cttcatgatc aatctcttcg gaagtgcagg agtaaaattc 480tagagtttgt ctggccttct gaagcgtgtt gctgatggct cgcagcaggg tttgggagtg 540gttgaggcac tggaacatcc ccggggatgg agtaggggtt ggcaagtttc tagatccgcc 600gccaccgcca ccactgcagg acacggatgc ccagttgctc caggatgagc tatagtagcg 660gtctctggct tgcacgcgga tcttggcatc cttgtggcac acgaccttgg ctgaggtctt 720gtccacggag agtctgtctt tcttttctct gttgttcttg ccctggacct gtacgccaaa 780tgttaaggag aagtaggaat gtggggtgct ccaggtgtca gggtattccc agctcacttc 840cacatgccga gaatttttta atggcttcag ttgcaggttc ttgggtgggt ccggtttgat 900gatgtccctg atgaagaagc tgctggtgta gttttcgtac ttgagcttgt gaatagcgtc 960caccacgact tcaatgggta ggctctcctc ggcagccggg caggcactgc cctcctgaca 1020ctccactgtg tacttcttat aatccctgtt gtccactctg accttctctg ctgagagtgt 1080cgctgctcca caagtcacct cttgggggtc agaggagcct ctgctgcttt tgacagtgaa 1140tttcaaatcg gtactgattg ccgtcagcca ccagcaggtg aaacgtccag aataattctt 1200tgcctcacat tttagaaaga tcttattttt ggattctttc tgttccctta agatatcagt 1260ggaccaaatt ccatcttcct ttttgtgtat caggaggaac gaatggctca gaacctcgcc 1320tcctttatga caggtatact ggccagcatc tgcaaattct ttgacttgga tggtcagagt 1380tttaccagag cctaggactt cactgctctg gtcagaggtc caggtgatgt catcttcttc 1440aggagtattg caggtgagga ccaccatttc tccgggggca tcagggtgcc agtccaactc 1500tacaacataa acgtttttct ccagttccca tat 1533 46 666 DNA Canis familiarisCDS (1)..(666) 46 atg tgc ccg ccg cgc ggc ctc ctc ctt gtg acc atc ctggtc ctg cta 48 Met Cys Pro Pro Arg Gly Leu Leu Leu Val Thr Ile Leu ValLeu Leu 1 5 10 15 agc cac ctg gac cac ctt act tgg gcc agg agc ctc cccaca gcc tca 96 Ser His Leu Asp His Leu Thr Trp Ala Arg Ser Leu Pro ThrAla Ser 20 25 30 ccg agc cca gga ata ttc cag tgc ctc aac cac tcc caa aacctg ctg 144 Pro Ser Pro Gly Ile Phe Gln Cys Leu Asn His Ser Gln Asn LeuLeu 35 40 45 aga gcc gtc agc aac acg ctt cag aag gcc aga caa act cta gaatta 192 Arg Ala Val Ser Asn Thr Leu Gln Lys Ala Arg Gln Thr Leu Glu Leu50 55 60 tat tcc tgc act tcc gaa gag att gat cat gaa gat atc aca aag gat240 Tyr Ser Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp 6570 75 80 aaa acc agc aca gtg gag gcc tgc tta cca ctg gaa tta acc atg aat288 Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Met Asn 8590 95 gag agt tgc ctg gct tcc aga gag atc tct ttg ata act aac ggg agt336 Glu Ser Cys Leu Ala Ser Arg Glu Ile Ser Leu Ile Thr Asn Gly Ser 100105 110 tgc ctg gcc tct gga aag gcc tct ttt atg acg gtc ctg tgc ctt agc384 Cys Leu Ala Ser Gly Lys Ala Ser Phe Met Thr Val Leu Cys Leu Ser 115120 125 agc atc tat gag gac ttg aag atg tac cag atg gaa ttc aag gcc atg432 Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Met Glu Phe Lys Ala Met 130135 140 aac gca aag ctt tta atg gat ccc aag agg cag atc ttt ctg gat caa480 Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln 145150 155 160 aac atg ctg aca gct atc gat gag ctg tta cag gcc ctg aat ttcaac 528 Asn Met Leu Thr Ala Ile Asp Glu Leu Leu Gln Ala Leu Asn Phe Asn165 170 175 agt gtg act gtg cca cag aaa tcc tcc ctt gaa gag ccg gat ttttat 576 Ser Val Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr180 185 190 aaa act aaa atc aag ctc tgc ata ctt ctt cat gct ttc aga attcgt 624 Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg195 200 205 gcg gtg acc atc gat aga atg atg agt tat ctg aat tct tcc 666Ala Val Thr Ile Asp Arg Met Met Ser Tyr Leu Asn Ser Ser 210 215 220 47222 PRT Canis familiaris 47 Met Cys Pro Pro Arg Gly Leu Leu Leu Val ThrIle Leu Val Leu Leu 1 5 10 15 Ser His Leu Asp His Leu Thr Trp Ala ArgSer Leu Pro Thr Ala Ser 20 25 30 Pro Ser Pro Gly Ile Phe Gln Cys Leu AsnHis Ser Gln Asn Leu Leu 35 40 45 Arg Ala Val Ser Asn Thr Leu Gln Lys AlaArg Gln Thr Leu Glu Leu 50 55 60 Tyr Ser Cys Thr Ser Glu Glu Ile Asp HisGlu Asp Ile Thr Lys Asp 65 70 75 80 Lys Thr Ser Thr Val Glu Ala Cys LeuPro Leu Glu Leu Thr Met Asn 85 90 95 Glu Ser Cys Leu Ala Ser Arg Glu IleSer Leu Ile Thr Asn Gly Ser 100 105 110 Cys Leu Ala Ser Gly Lys Ala SerPhe Met Thr Val Leu Cys Leu Ser 115 120 125 Ser Ile Tyr Glu Asp Leu LysMet Tyr Gln Met Glu Phe Lys Ala Met 130 135 140 Asn Ala Lys Leu Leu MetAsp Pro Lys Arg Gln Ile Phe Leu Asp Gln 145 150 155 160 Asn Met Leu ThrAla Ile Asp Glu Leu Leu Gln Ala Leu Asn Phe Asn 165 170 175 Ser Val ThrVal Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr 180 185 190 Lys ThrLys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg 195 200 205 AlaVal Thr Ile Asp Arg Met Met Ser Tyr Leu Asn Ser Ser 210 215 220 48 666DNA Canis familiaris 48 ggaagaattc agataactca tcattctatc gatggtcaccgcacgaattc tgaaagcatg 60 aagaagtatg cagagcttga ttttagtttt ataaaaatccggctcttcaa gggaggattt 120 ctgtggcaca gtcacactgt tgaaattcag ggcctgtaacagctcatcga tagctgtcag 180 catgttttga tccagaaaga tctgcctctt gggatccattaaaagctttg cgttcatggc 240 cttgaattcc atctggtaca tcttcaagtc ctcatagatgctgctaaggc acaggaccgt 300 cataaaagag gcctttccag aggccaggca actcccgttagttatcaaag agatctctct 360 ggaagccagg caactctcat tcatggttaa ttccagtggtaagcaggcct ccactgtgct 420 ggttttatcc tttgtgatat cttcatgatc aatctcttcggaagtgcagg aatataattc 480 tagagtttgt ctggccttct gaagcgtgtt gctgacggctctcagcaggt tttgggagtg 540 gttgaggcac tggaatattc ctgggctcgg tgaggctgtggggaggctcc tggcccaagt 600 aaggtggtcc aggtggctta gcaggaccag gatggtcacaaggaggaggc cgcgcggcgg 660 gcacat 666 49 591 DNA Canis familiaris CDS(1)..(591) 49 agg agc ctc ccc aca gcc tca ccg agc cca gga ata ttc cagtgc ctc 48 Arg Ser Leu Pro Thr Ala Ser Pro Ser Pro Gly Ile Phe Gln CysLeu 1 5 10 15 aac cac tcc caa aac ctg ctg aga gcc gtc agc aac acg cttcag aag 96 Asn His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Thr Leu GlnLys 20 25 30 gcc aga caa act cta gaa tta tat tcc tgc act tcc gaa gag attgat 144 Ala Arg Gln Thr Leu Glu Leu Tyr Ser Cys Thr Ser Glu Glu Ile Asp35 40 45 cat gaa gat atc aca aag gat aaa acc agc aca gtg gag gcc tgc tta192 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 5055 60 cca ctg gaa tta acc atg aat gag agt tgc ctg gct tcc aga gag atc240 Pro Leu Glu Leu Thr Met Asn Glu Ser Cys Leu Ala Ser Arg Glu Ile 6570 75 80 tct ttg ata act aac ggg agt tgc ctg gcc tct gga aag gcc tct ttt288 Ser Leu Ile Thr Asn Gly Ser Cys Leu Ala Ser Gly Lys Ala Ser Phe 8590 95 atg acg gtc ctg tgc ctt agc agc atc tat gag gac ttg aag atg tac336 Met Thr Val Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100105 110 cag atg gaa ttc aag gcc atg aac gca aag ctt tta atg gat ccc aag384 Gln Met Glu Phe Lys Ala Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115120 125 agg cag atc ttt ctg gat caa aac atg ctg aca gct atc gat gag ctg432 Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Thr Ala Ile Asp Glu Leu 130135 140 tta cag gcc ctg aat ttc aac agt gtg act gtg cca cag aaa tcc tcc480 Leu Gln Ala Leu Asn Phe Asn Ser Val Thr Val Pro Gln Lys Ser Ser 145150 155 160 ctt gaa gag ccg gat ttt tat aaa act aaa atc aag ctc tgc atactt 528 Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu165 170 175 ctt cat gct ttc aga att cgt gcg gtg acc atc gat aga atg atgagt 576 Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Met Met Ser180 185 190 tat ctg aat tct tcc 591 Tyr Leu Asn Ser Ser 195 50 197 PRTCanis familiaris 50 Arg Ser Leu Pro Thr Ala Ser Pro Ser Pro Gly Ile PheGln Cys Leu 1 5 10 15 Asn His Ser Gln Asn Leu Leu Arg Ala Val Ser AsnThr Leu Gln Lys 20 25 30 Ala Arg Gln Thr Leu Glu Leu Tyr Ser Cys Thr SerGlu Glu Ile Asp 35 40 45 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr ValGlu Ala Cys Leu 50 55 60 Pro Leu Glu Leu Thr Met Asn Glu Ser Cys Leu AlaSer Arg Glu Ile 65 70 75 80 Ser Leu Ile Thr Asn Gly Ser Cys Leu Ala SerGly Lys Ala Ser Phe 85 90 95 Met Thr Val Leu Cys Leu Ser Ser Ile Tyr GluAsp Leu Lys Met Tyr 100 105 110 Gln Met Glu Phe Lys Ala Met Asn Ala LysLeu Leu Met Asp Pro Lys 115 120 125 Arg Gln Ile Phe Leu Asp Gln Asn MetLeu Thr Ala Ile Asp Glu Leu 130 135 140 Leu Gln Ala Leu Asn Phe Asn SerVal Thr Val Pro Gln Lys Ser Ser 145 150 155 160 Leu Glu Glu Pro Asp PheTyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 165 170 175 Leu His Ala Phe ArgIle Arg Ala Val Thr Ile Asp Arg Met Met Ser 180 185 190 Tyr Leu Asn SerSer 195 51 591 DNA Canis familiaris 51 ggaagaattc agataactca tcattctatcgatggtcacc gcacgaattc tgaaagcatg 60 aagaagtatg cagagcttga ttttagttttataaaaatcc ggctcttcaa gggaggattt 120 ctgtggcaca gtcacactgt tgaaattcagggcctgtaac agctcatcga tagctgtcag 180 catgttttga tccagaaaga tctgcctcttgggatccatt aaaagctttg cgttcatggc 240 cttgaattcc atctggtaca tcttcaagtcctcatagatg ctgctaaggc acaggaccgt 300 cataaaagag gcctttccag aggccaggcaactcccgtta gttatcaaag agatctctct 360 ggaagccagg caactctcat tcatggttaattccagtggt aagcaggcct ccactgtgct 420 ggttttatcc tttgtgatat cttcatgatcaatctcttcg gaagtgcagg aatataattc 480 tagagtttgt ctggccttct gaagcgtgttgctgacggct ctcagcaggt tttgggagtg 540 gttgaggcac tggaatattc ctgggctcggtgaggctgtg gggaggctcc t 591 52 921 DNA Canis familiaris CDS (1)..(921)52 ata tgg gaa ctg gag aaa gat gtt tat gtt gta gag ttg gac tgg cac 48Ile Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Leu Asp Trp His 1 5 1015 cct gat gcc ccc gga gaa atg gtg gtc ctc acc tgc cat acc cct gaa 96Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys His Thr Pro Glu 20 25 30gaa gat gac atc act tgg acc tca gcg cag agc agt gaa gtc cta ggt 144 GluAsp Asp Ile Thr Trp Thr Ser Ala Gln Ser Ser Glu Val Leu Gly 35 40 45 tctggt aaa act ctg acc atc caa gtc aaa gaa ttt gga gat gct ggc 192 Ser GlyLys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 cag tatacc tgc cat aaa gga ggc aag gtt ctg agc cgc tca ctc ctg 240 Gln Tyr ThrCys His Lys Gly Gly Lys Val Leu Ser Arg Ser Leu Leu 65 70 75 80 ttg attcac aaa aaa gaa gat gga att tgg tcc act gat atc tta aag 288 Leu Ile HisLys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 gaa cag aaagaa tcc aaa aat aag atc ttt ctg aaa tgt gag gca aag 336 Glu Gln Lys GluSer Lys Asn Lys Ile Phe Leu Lys Cys Glu Ala Lys 100 105 110 aat tat tctgga cgt ttc aca tgc tgg tgg ctg acg gca atc agt act 384 Asn Tyr Ser GlyArg Phe Thr Cys Trp Trp Leu Thr Ala Ile Ser Thr 115 120 125 gat ttg aaattc agt gtc aaa agt agc aga ggc ttc tct gac ccc caa 432 Asp Leu Lys PheSer Val Lys Ser Ser Arg Gly Phe Ser Asp Pro Gln 130 135 140 ggg gtg acatgt gga gca gtg aca ctt tca gca gag agg gtc aga gtg 480 Gly Val Thr CysGly Ala Val Thr Leu Ser Ala Glu Arg Val Arg Val 145 150 155 160 gac aacagg gat tat aag aag tac aca gtg gag tgt cag gag ggc agt 528 Asp Asn ArgAsp Tyr Lys Lys Tyr Thr Val Glu Cys Gln Glu Gly Ser 165 170 175 gcc tgcccc tct gcc gag gag agc cta ccc atc gag gtc gtg gtg gat 576 Ala Cys ProSer Ala Glu Glu Ser Leu Pro Ile Glu Val Val Val Asp 180 185 190 gct attcac aag ctc aag tat gaa aac tac acc agc agc ttc ttc atc 624 Ala Ile HisLys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile 195 200 205 aga gacatc atc aaa cca gac cca ccc aca aac ctg cag ctg aag cca 672 Arg Asp IleIle Lys Pro Asp Pro Pro Thr Asn Leu Gln Leu Lys Pro 210 215 220 ttg aaaaat tct cgg cac gtg gag gtc agc tgg gaa tac ccc gac acc 720 Leu Lys AsnSer Arg His Val Glu Val Ser Trp Glu Tyr Pro Asp Thr 225 230 235 240 tggagc acc cca cat tcc tac ttc tcc ctg aca ttt tgc ata cag gcc 768 Trp SerThr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Ile Gln Ala 245 250 255 cagggc aag aac aat aga gaa aag aaa gat aga ctc tgc gtg gac aag 816 Gln GlyLys Asn Asn Arg Glu Lys Lys Asp Arg Leu Cys Val Asp Lys 260 265 270 acctca gcc aag gtc gtg tgc cac aag gat gcc aag atc cgc gtg caa 864 Thr SerAla Lys Val Val Cys His Lys Asp Ala Lys Ile Arg Val Gln 275 280 285 gcccga gac cgc tac tat agt tca tcc tgg agc gac tgg gca tct gtg 912 Ala ArgAsp Arg Tyr Tyr Ser Ser Ser Trp Ser Asp Trp Ala Ser Val 290 295 300 tcctgc agt 921 Ser Cys Ser 305 53 307 PRT Canis familiaris 53 Ile Trp GluLeu Glu Lys Asp Val Tyr Val Val Glu Leu Asp Trp His 1 5 10 15 Pro AspAla Pro Gly Glu Met Val Val Leu Thr Cys His Thr Pro Glu 20 25 30 Glu AspAsp Ile Thr Trp Thr Ser Ala Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser GlyLys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln TyrThr Cys His Lys Gly Gly Lys Val Leu Ser Arg Ser Leu Leu 65 70 75 80 LeuIle His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 GluGln Lys Glu Ser Lys Asn Lys Ile Phe Leu Lys Cys Glu Ala Lys 100 105 110Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Ala Ile Ser Thr 115 120125 Asp Leu Lys Phe Ser Val Lys Ser Ser Arg Gly Phe Ser Asp Pro Gln 130135 140 Gly Val Thr Cys Gly Ala Val Thr Leu Ser Ala Glu Arg Val Arg Val145 150 155 160 Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val Glu Cys Gln GluGly Ser 165 170 175 Ala Cys Pro Ser Ala Glu Glu Ser Leu Pro Ile Glu ValVal Val Asp 180 185 190 Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr Thr SerSer Phe Phe Ile 195 200 205 Arg Asp Ile Ile Lys Pro Asp Pro Pro Thr AsnLeu Gln Leu Lys Pro 210 215 220 Leu Lys Asn Ser Arg His Val Glu Val SerTrp Glu Tyr Pro Asp Thr 225 230 235 240 Trp Ser Thr Pro His Ser Tyr PheSer Leu Thr Phe Cys Ile Gln Ala 245 250 255 Gln Gly Lys Asn Asn Arg GluLys Lys Asp Arg Leu Cys Val Asp Lys 260 265 270 Thr Ser Ala Lys Val ValCys His Lys Asp Ala Lys Ile Arg Val Gln 275 280 285 Ala Arg Asp Arg TyrTyr Ser Ser Ser Trp Ser Asp Trp Ala Ser Val 290 295 300 Ser Cys Ser 30554 921 DNA Canis familiaris 54 actgcaggac acagatgccc agtcgctccaggatgaacta tagtagcggt ctcgggcttg 60 cacgcggatc ttggcatcct tgtggcacacgaccttggct gaggtcttgt ccacgcagag 120 tctatctttc ttttctctat tgttcttgccctgggcctgt atgcaaaatg tcagggagaa 180 gtaggaatgt ggggtgctcc aggtgtcggggtattcccag ctgacctcca cgtgccgaga 240 atttttcaat ggcttcagct gcaggtttgtgggtgggtct ggtttgatga tgtctctgat 300 gaagaagctg ctggtgtagt tttcatacttgagcttgtga atagcatcca ccacgacctc 360 gatgggtagg ctctcctcgg cagaggggcaggcactgccc tcctgacact ccactgtgta 420 cttcttataa tccctgttgt ccactctgaccctctctgct gaaagtgtca ctgctccaca 480 tgtcacccct tgggggtcag agaagcctctgctacttttg acactgaatt tcaaatcagt 540 actgattgcc gtcagccacc agcatgtgaaacgtccagaa taattctttg cctcacattt 600 cagaaagatc ttatttttgg attctttctgttcctttaag atatcagtgg accaaattcc 660 atcttctttt ttgtgaatca acaggagtgagcggctcaga accttgcctc ctttatggca 720 ggtatactgg ccagcatctc caaattctttgacttggatg gtcagagttt taccagaacc 780 taggacttca ctgctctgcg ctgaggtccaagtgatgtca tcttcttcag gggtatggca 840 ggtgaggacc accatttctc cgggggcatcagggtgccag tccaactcta caacataaac 900 atctttctcc agttcccata t 921 55 985DNA Felis catus CDS (1)..(984) 55 atg cat cct cag cag ttg gtc atc gcctgg ttt tcc ctg gtt ttg ctg 48 Met His Pro Gln Gln Leu Val Ile Ala TrpPhe Ser Leu Val Leu Leu 1 5 10 15 gca cct ccc ctc atg gcc ata tgg gaactg gag aaa aac gtt tat gtt 96 Ala Pro Pro Leu Met Ala Ile Trp Glu LeuGlu Lys Asn Val Tyr Val 20 25 30 gta gag ttg gac tgg cac cct gat gcc cccgga gaa atg gtg gtc ctc 144 Val Glu Leu Asp Trp His Pro Asp Ala Pro GlyGlu Met Val Val Leu 35 40 45 acc tgc aat act cct gaa gaa gat gac atc acctgg acc tct gac cag 192 Thr Cys Asn Thr Pro Glu Glu Asp Asp Ile Thr TrpThr Ser Asp Gln 50 55 60 agc agt gaa gtc cta ggc tct ggt aaa act ctg accatc caa gtc aaa 240 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr IleGln Val Lys 65 70 75 80 gaa ttt gca gat gct ggc cag tat acc tgt cat aaagga ggc gag gtt 288 Glu Phe Ala Asp Ala Gly Gln Tyr Thr Cys His Lys GlyGly Glu Val 85 90 95 ctg agc cat tcg ttc ctc ctg ata cac aaa aag gaa gatgga att tgg 336 Leu Ser His Ser Phe Leu Leu Ile His Lys Lys Glu Asp GlyIle Trp 100 105 110 tcc act gat atc tta agg gaa cag aaa gaa tcc aaa aataag atc ttt 384 Ser Thr Asp Ile Leu Arg Glu Gln Lys Glu Ser Lys Asn LysIle Phe 115 120 125 cta aaa tgt gag gca aag aat tat tct gga cgt ttc acctgc tgg tgg 432 Leu Lys Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr CysTrp Trp 130 135 140 ctg acg gca atc agt acc gat ttg aaa ttc act gtc aaaagc agc aga 480 Leu Thr Ala Ile Ser Thr Asp Leu Lys Phe Thr Val Lys SerSer Arg 145 150 155 160 ggc tcc tct gac ccc caa ggg gtg act tgt gga gcagcg aca ctc tca 528 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala AlaThr Leu Ser 165 170 175 gca gag aag gtc aga gtg gac aac agg gat tat aagaag tac aca gtg 576 Ala Glu Lys Val Arg Val Asp Asn Arg Asp Tyr Lys LysTyr Thr Val 180 185 190 gag tgt cag gag ggc agt gcc tgc ccg gct gcc gaggag agc cta ccc 624 Glu Cys Gln Glu Gly Ser Ala Cys Pro Ala Ala Glu GluSer Leu Pro 195 200 205 att gaa gtc gtg gtg gac gct att cac aag ctc aagtac gaa aac tac 672 Ile Glu Val Val Val Asp Ala Ile His Lys Leu Lys TyrGlu Asn Tyr 210 215 220 acc agc agc ttc ttc atc agg gac atc atc aaa ccggac cca ccc aag 720 Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro AspPro Pro Lys 225 230 235 240 aac ctg caa ctg aag cca tta aaa aat tct cggcat gtg gaa gtg agc 768 Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg HisVal Glu Val Ser 245 250 255 tgg gaa tac cct gac acc tgg agc acc cca cattcc tac ttc tcc tta 816 Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His SerTyr Phe Ser Leu 260 265 270 aca ttt ggc gta cag gtc cag ggc aag aac aacaga gaa aag aaa gac 864 Thr Phe Gly Val Gln Val Gln Gly Lys Asn Asn ArgGlu Lys Lys Asp 275 280 285 aga ctc tcc gtg gac aag acc tca gcc aag gtcgtg tgc cac aag gat 912 Arg Leu Ser Val Asp Lys Thr Ser Ala Lys Val ValCys His Lys Asp 290 295 300 gcc aag atc cgc gtg caa gcc aga gac cgc tactat agc tca tcc tgg 960 Ala Lys Ile Arg Val Gln Ala Arg Asp Arg Tyr TyrSer Ser Ser Trp 305 310 315 320 agc aac tgg gca tcc gtg tcc tgc a 985Ser Asn Trp Ala Ser Val Ser Cys 325 56 328 PRT Felis catus 56 Met HisPro Gln Gln Leu Val Ile Ala Trp Phe Ser Leu Val Leu Leu 1 5 10 15 AlaPro Pro Leu Met Ala Ile Trp Glu Leu Glu Lys Asn Val Tyr Val 20 25 30 ValGlu Leu Asp Trp His Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 ThrCys Asn Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 SerSer Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80Glu Phe Ala Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95Leu Ser His Ser Phe Leu Leu Ile His Lys Lys Glu Asp Gly Ile Trp 100 105110 Ser Thr Asp Ile Leu Arg Glu Gln Lys Glu Ser Lys Asn Lys Ile Phe 115120 125 Leu Lys Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp130 135 140 Leu Thr Ala Ile Ser Thr Asp Leu Lys Phe Thr Val Lys Ser SerArg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala AlaThr Leu Ser 165 170 175 Ala Glu Lys Val Arg Val Asp Asn Arg Asp Tyr LysLys Tyr Thr Val 180 185 190 Glu Cys Gln Glu Gly Ser Ala Cys Pro Ala AlaGlu Glu Ser Leu Pro 195 200 205 Ile Glu Val Val Val Asp Ala Ile His LysLeu Lys Tyr Glu Asn Tyr 210 215 220 Thr Ser Ser Phe Phe Ile Arg Asp IleIle Lys Pro Asp Pro Pro Lys 225 230 235 240 Asn Leu Gln Leu Lys Pro LeuLys Asn Ser Arg His Val Glu Val Ser 245 250 255 Trp Glu Tyr Pro Asp ThrTrp Ser Thr Pro His Ser Tyr Phe Ser Leu 260 265 270 Thr Phe Gly Val GlnVal Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285 Arg Leu Ser ValAsp Lys Thr Ser Ala Lys Val Val Cys His Lys Asp 290 295 300 Ala Lys IleArg Val Gln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 SerAsn Trp Ala Ser Val Ser Cys 325 57 985 DNA Felis catus 57 tgcaggacacggatgcccag ttgctccagg atgagctata gtagcggtct ctggcttgca 60 cgcggatcttggcatccttg tggcacacga ccttggctga ggtcttgtcc acggagagtc 120 tgtctttcttttctctgttg ttcttgccct ggacctgtac gccaaatgtt aaggagaagt 180 aggaatgtggggtgctccag gtgtcagggt attcccagct cacttccaca tgccgagaat 240 tttttaatggcttcagttgc aggttcttgg gtgggtccgg tttgatgatg tccctgatga 300 agaagctgctggtgtagttt tcgtacttga gcttgtgaat agcgtccacc acgacttcaa 360 tgggtaggctctcctcggca gccgggcagg cactgccctc ctgacactcc actgtgtact 420 tcttataatccctgttgtcc actctgacct tctctgctga gagtgtcgct gctccacaag 480 tcaccccttgggggtcagag gagcctctgc tgcttttgac agtgaatttc aaatcggtac 540 tgattgccgtcagccaccag caggtgaaac gtccagaata attctttgcc tcacatttta 600 gaaagatcttatttttggat tctttctgtt cccttaagat atcagtggac caaattccat 660 cttcctttttgtgtatcagg aggaacgaat ggctcagaac ctcgcctcct ttatgacagg 720 tatactggccagcatctgca aattctttga cttggatggt cagagtttta ccagagccta 780 ggacttcactgctctggtca gaggtccagg tgatgtcatc ttcttcagga gtattgcagg 840 tgaggaccaccatttctccg ggggcatcag ggtgccagtc caactctaca acataaacgt 900 ttttctccagttcccatatg gccatgaggg gaggtgccag caaaaccagg gaaaaccagg 960 cgatgaccaactgctgagga tgcat 985 58 987 DNA Canis familiaris CDS (1)..(987) 58 atgcac cct cag cag ttg gtc atc tcc tgg ttt tcc ctc gtt ttg ctg 48 Met HisPro Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Leu Leu 1 5 10 15 gcgtct ccc ctc atg gcc ata tgg gaa ctg gag aaa gat gtt tat gtt 96 Ala SerPro Leu Met Ala Ile Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 gta gagttg gac tgg cac cct gat gcc ccc gga gaa atg gtg gtc ctc 144 Val Glu LeuAsp Trp His Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 acc tgc catacc cct gaa gaa gat gac atc act tgg acc tca gcg cag 192 Thr Cys His ThrPro Glu Glu Asp Asp Ile Thr Trp Thr Ser Ala Gln 50 55 60 agc agt gaa gtccta ggt tct ggt aaa act ctg acc atc caa gtc aaa 240 Ser Ser Glu Val LeuGly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 gaa ttt gga gatgct ggc cag tat acc tgc cat aaa gga ggc aag gtt 288 Glu Phe Gly Asp AlaGly Gln Tyr Thr Cys His Lys Gly Gly Lys Val 85 90 95 ctg agc cgc tca ctcctg ttg att cac aaa aaa gaa gat gga att tgg 336 Leu Ser Arg Ser Leu LeuLeu Ile His Lys Lys Glu Asp Gly Ile Trp 100 105 110 tcc act gat atc ttaaag gaa cag aaa gaa tcc aaa aat aag atc ttt 384 Ser Thr Asp Ile Leu LysGlu Gln Lys Glu Ser Lys Asn Lys Ile Phe 115 120 125 ctg aaa tgt gag gcaaag aat tat tct gga cgt ttc aca tgc tgg tgg 432 Leu Lys Cys Glu Ala LysAsn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 ctg acg gca atc agtact gat ttg aaa ttc agt gtc aaa agt agc aga 480 Leu Thr Ala Ile Ser ThrAsp Leu Lys Phe Ser Val Lys Ser Ser Arg 145 150 155 160 ggc ttc tct gacccc caa ggg gtg aca tgt gga gca gtg aca ctt tca 528 Gly Phe Ser Asp ProGln Gly Val Thr Cys Gly Ala Val Thr Leu Ser 165 170 175 gca gag agg gtcaga gtg gac aac agg gat tat aag aag tac aca gtg 576 Ala Glu Arg Val ArgVal Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val 180 185 190 gag tgt cag gagggc agt gcc tgc ccc tct gcc gag gag agc cta ccc 624 Glu Cys Gln Glu GlySer Ala Cys Pro Ser Ala Glu Glu Ser Leu Pro 195 200 205 atc gag gtc gtggtg gat gct att cac aag ctc aag tat gaa aac tac 672 Ile Glu Val Val ValAsp Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr 210 215 220 acc agc agc ttcttc atc aga gac atc atc aaa cca gac cca ccc aca 720 Thr Ser Ser Phe PheIle Arg Asp Ile Ile Lys Pro Asp Pro Pro Thr 225 230 235 240 aac ctg cagctg aag cca ttg aaa aat tct cgg cac gtg gag gtc agc 768 Asn Leu Gln LeuLys Pro Leu Lys Asn Ser Arg His Val Glu Val Ser 245 250 255 tgg gaa tacccc gac acc tgg agc acc cca cat tcc tac ttc tcc ctg 816 Trp Glu Tyr ProAsp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu 260 265 270 aca ttt tgcata cag gcc cag ggc aag aac aat aga gaa aag aaa gat 864 Thr Phe Cys IleGln Ala Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285 aga ctc tgcgtg gac aag acc tca gcc aag gtc gtg tgc cac aag gat 912 Arg Leu Cys ValAsp Lys Thr Ser Ala Lys Val Val Cys His Lys Asp 290 295 300 gcc aag atccgc gtg caa gcc cga gac cgc tac tat agt tca tcc tgg 960 Ala Lys Ile ArgVal Gln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 agc gactgg gca tct gtg tca tgc agt 987 Ser Asp Trp Ala Ser Val Ser Cys Ser 32559 329 PRT Canis familiaris 59 Met His Pro Gln Gln Leu Val Ile Ser TrpPhe Ser Leu Val Leu Leu 1 5 10 15 Ala Ser Pro Leu Met Ala Ile Trp GluLeu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp His Pro Asp AlaPro Gly Glu Met Val Val Leu 35 40 45 Thr Cys His Thr Pro Glu Glu Asp AspIle Thr Trp Thr Ser Ala Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly LysThr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln TyrThr Cys His Lys Gly Gly Lys Val 85 90 95 Leu Ser Arg Ser Leu Leu Leu IleHis Lys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys GluGln Lys Glu Ser Lys Asn Lys Ile Phe 115 120 125 Leu Lys Cys Glu Ala LysAsn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Ala Ile SerThr Asp Leu Lys Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Phe SerAsp Pro Gln Gly Val Thr Cys Gly Ala Val Thr Leu Ser 165 170 175 Ala GluArg Val Arg Val Asp Asn Arg Asp Tyr Lys Lys Tyr Thr Val 180 185 190 GluCys Gln Glu Gly Ser Ala Cys Pro Ser Ala Glu Glu Ser Leu Pro 195 200 205Ile Glu Val Val Val Asp Ala Ile His Lys Leu Lys Tyr Glu Asn Tyr 210 215220 Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Thr 225230 235 240 Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg His Val Glu ValSer 245 250 255 Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr PheSer Leu 260 265 270 Thr Phe Cys Ile Gln Ala Gln Gly Lys Asn Asn Arg GluLys Lys Asp 275 280 285 Arg Leu Cys Val Asp Lys Thr Ser Ala Lys Val ValCys His Lys Asp 290 295 300 Ala Lys Ile Arg Val Gln Ala Arg Asp Arg TyrTyr Ser Ser Ser Trp 305 310 315 320 Ser Asp Trp Ala Ser Val Ser Cys Ser325 60 987 DNA Canis familiaris 60 actgcatgac acagatgccc agtcgctccaggatgaacta tagtagcggt ctcgggcttg 60 cacgcggatc ttggcatcct tgtggcacacgaccttggct gaggtcttgt ccacgcagag 120 tctatctttc ttttctctat tgttcttgccctgggcctgt atgcaaaatg tcagggagaa 180 gtaggaatgt ggggtgctcc aggtgtcggggtattcccag ctgacctcca cgtgccgaga 240 atttttcaat ggcttcagct gcaggtttgtgggtgggtct ggtttgatga tgtctctgat 300 gaagaagctg ctggtgtagt tttcatacttgagcttgtga atagcatcca ccacgacctc 360 gatgggtagg ctctcctcgg cagaggggcaggcactgccc tcctgacact ccactgtgta 420 cttcttataa tccctgttgt ccactctgaccctctctgct gaaagtgtca ctgctccaca 480 tgtcacccct tgggggtcag agaagcctctgctacttttg acactgaatt tcaaatcagt 540 actgattgcc gtcagccacc agcatgtgaaacgtccagaa taattctttg cctcacattt 600 cagaaagatc ttatttttgg attctttctgttcctttaag atatcagtgg accaaattcc 660 atcttctttt ttgtgaatca acaggagtgagcggctcaga accttgcctc ctttatggca 720 ggtatactgg ccagcatctc caaattctttgacttggatg gtcagagttt taccagaacc 780 taggacttca ctgctctgcg ctgaggtccaagtgatgtca tcttcttcag gggtatggca 840 ggtgaggacc accatttctc cgggggcatcagggtgccag tccaactcta caacataaac 900 atctttctcc agttcccata tggccatgaggggagacgcc agcaaaacga gggaaaacca 960 ggagatgacc aactgctgag ggtgcat 98761 1599 DNA Canis familiaris CDS (1)..(1599) 61 atg cac cct cag cag ttggtc atc tcc tgg ttt tcc ctc gtt ttg ctg 48 Met His Pro Gln Gln Leu ValIle Ser Trp Phe Ser Leu Val Leu Leu 1 5 10 15 gcg tct ccc ctc atg gccata tgg gaa ctg gag aaa gat gtt tat gtt 96 Ala Ser Pro Leu Met Ala IleTrp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 gta gag ttg gac tgg cac cctgat gcc ccc gga gaa atg gtg gtc ctc 144 Val Glu Leu Asp Trp His Pro AspAla Pro Gly Glu Met Val Val Leu 35 40 45 acc tgc cat acc cct gaa gaa gatgac atc act tgg acc tca gcg cag 192 Thr Cys His Thr Pro Glu Glu Asp AspIle Thr Trp Thr Ser Ala Gln 50 55 60 agc agt gaa gtc cta ggt tct ggt aaaact ctg acc atc caa gtc aaa 240 Ser Ser Glu Val Leu Gly Ser Gly Lys ThrLeu Thr Ile Gln Val Lys 65 70 75 80 gaa ttt gga gat gct ggc cag tat acctgc cat aaa gga ggc aag gtt 288 Glu Phe Gly Asp Ala Gly Gln Tyr Thr CysHis Lys Gly Gly Lys Val 85 90 95 ctg agc cgc tca ctc ctg ttg att cac aaaaaa gaa gat gga att tgg 336 Leu Ser Arg Ser Leu Leu Leu Ile His Lys LysGlu Asp Gly Ile Trp 100 105 110 tcc act gat atc tta aag gaa cag aaa gaatcc aaa aat aag atc ttt 384 Ser Thr Asp Ile Leu Lys Glu Gln Lys Glu SerLys Asn Lys Ile Phe 115 120 125 ctg aaa tgt gag gca aag aat tat tct ggacgt ttc aca tgc tgg tgg 432 Leu Lys Cys Glu Ala Lys Asn Tyr Ser Gly ArgPhe Thr Cys Trp Trp 130 135 140 ctg acg gca atc agt act gat ttg aaa ttcagt gtc aaa agt agc aga 480 Leu Thr Ala Ile Ser Thr Asp Leu Lys Phe SerVal Lys Ser Ser Arg 145 150 155 160 ggc ttc tct gac ccc caa ggg gtg acatgt gga gca gtg aca ctt tca 528 Gly Phe Ser Asp Pro Gln Gly Val Thr CysGly Ala Val Thr Leu Ser 165 170 175 gca gag agg gtc aga gtg gac aac agggat tat aag aag tac aca gtg 576 Ala Glu Arg Val Arg Val Asp Asn Arg AspTyr Lys Lys Tyr Thr Val 180 185 190 gag tgt cag gag ggc agt gcc tgc ccctct gcc gag gag agc cta ccc 624 Glu Cys Gln Glu Gly Ser Ala Cys Pro SerAla Glu Glu Ser Leu Pro 195 200 205 atc gag gtc gtg gtg gat gct att cacaag ctc aag tat gaa aac tac 672 Ile Glu Val Val Val Asp Ala Ile His LysLeu Lys Tyr Glu Asn Tyr 210 215 220 acc agc agc ttc ttc atc aga gac atcatc aaa cca gac cca ccc aca 720 Thr Ser Ser Phe Phe Ile Arg Asp Ile IleLys Pro Asp Pro Pro Thr 225 230 235 240 aac ctg cag ctg aag cca ttg aaaaat tct cgg cac gtg gag gtc agc 768 Asn Leu Gln Leu Lys Pro Leu Lys AsnSer Arg His Val Glu Val Ser 245 250 255 tgg gaa tac ccc gac acc tgg agcacc cca cat tcc tac ttc tcc ctg 816 Trp Glu Tyr Pro Asp Thr Trp Ser ThrPro His Ser Tyr Phe Ser Leu 260 265 270 aca ttt tgc ata cag gcc cag ggcaag aac aat aga gaa aag aaa gat 864 Thr Phe Cys Ile Gln Ala Gln Gly LysAsn Asn Arg Glu Lys Lys Asp 275 280 285 aga ctc tgc gtg gac aag acc tcagcc aag gtc gtg tgc cac aag gat 912 Arg Leu Cys Val Asp Lys Thr Ser AlaLys Val Val Cys His Lys Asp 290 295 300 gcc aag atc cgc gtg caa gcc cgagac cgc tac tat agt tca tcc tgg 960 Ala Lys Ile Arg Val Gln Ala Arg AspArg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 agc gac tgg gca tct gtg tcatgc agt ggt ggc ggt ggc ggc gga tct 1008 Ser Asp Trp Ala Ser Val Ser CysSer Gly Gly Gly Gly Gly Gly Ser 325 330 335 aga aac ttg cca acc cct actcca tcc ccg ggt atg ttc caa tgt ttg 1056 Arg Asn Leu Pro Thr Pro Thr ProSer Pro Gly Met Phe Gln Cys Leu 340 345 350 aac cac tcc caa acc ttg ttgaga gcc gtc agc aac acg ctt cag aag 1104 Asn His Ser Gln Thr Leu Leu ArgAla Val Ser Asn Thr Leu Gln Lys 355 360 365 gcc aga caa act cta gaa ttatat tcc tgc act tcc gaa gag att gat 1152 Ala Arg Gln Thr Leu Glu Leu TyrSer Cys Thr Ser Glu Glu Ile Asp 370 375 380 cat gaa gat atc aca aag gataaa acc agc aca gtg gag gcc tgc tta 1200 His Glu Asp Ile Thr Lys Asp LysThr Ser Thr Val Glu Ala Cys Leu 385 390 395 400 cca ctg gaa tta acc atgaat gag agt tgc ctg gct tcc aga gag atc 1248 Pro Leu Glu Leu Thr Met AsnGlu Ser Cys Leu Ala Ser Arg Glu Ile 405 410 415 tct ttg ata act aac gggagt tgc ctg gcc tct gga aag gcc tct ttt 1296 Ser Leu Ile Thr Asn Gly SerCys Leu Ala Ser Gly Lys Ala Ser Phe 420 425 430 atg acg gtc ctg tgc cttagc agc atc tat gag gac ttg aag atg tac 1344 Met Thr Val Leu Cys Leu SerSer Ile Tyr Glu Asp Leu Lys Met Tyr 435 440 445 cag atg gaa ttc aag gccatg aac gca aag ctt tta atg gat ccc aag 1392 Gln Met Glu Phe Lys Ala MetAsn Ala Lys Leu Leu Met Asp Pro Lys 450 455 460 agg cag atc ttt ctg gatcaa aac atg ctg aca gct atc gat gag ctg 1440 Arg Gln Ile Phe Leu Asp GlnAsn Met Leu Thr Ala Ile Asp Glu Leu 465 470 475 480 tta cag gcc ctg aatttc aac agt gtg act gtg cca cag aaa tcc tcc 1488 Leu Gln Ala Leu Asn PheAsn Ser Val Thr Val Pro Gln Lys Ser Ser 485 490 495 ctt gaa gag ccg gatttt tat aaa act aaa atc aag ctc tgc ata ctt 1536 Leu Glu Glu Pro Asp PheTyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 500 505 510 ctt cat gct ttc agaatt cgt gcg gtg acc atc aat aga atg atg tcc 1584 Leu His Ala Phe Arg IleArg Ala Val Thr Ile Asn Arg Met Met Ser 515 520 525 tac ttg aac tct tcc1599 Tyr Leu Asn Ser Ser 530 62 533 PRT Canis familiaris 62 Met His ProGln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Leu Leu 1 5 10 15 Ala SerPro Leu Met Ala Ile Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val GluLeu Asp Trp His Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr CysHis Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Ala Gln 50 55 60 Ser SerGlu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 GluPhe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Lys Val 85 90 95 LeuSer Arg Ser Leu Leu Leu Ile His Lys Lys Glu Asp Gly Ile Trp 100 105 110Ser Thr Asp Ile Leu Lys Glu Gln Lys Glu Ser Lys Asn Lys Ile Phe 115 120125 Leu Lys Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130135 140 Leu Thr Ala Ile Ser Thr Asp Leu Lys Phe Ser Val Lys Ser Ser Arg145 150 155 160 Gly Phe Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Val ThrLeu Ser 165 170 175 Ala Glu Arg Val Arg Val Asp Asn Arg Asp Tyr Lys LysTyr Thr Val 180 185 190 Glu Cys Gln Glu Gly Ser Ala Cys Pro Ser Ala GluGlu Ser Leu Pro 195 200 205 Ile Glu Val Val Val Asp Ala Ile His Lys LeuLys Tyr Glu Asn Tyr 210 215 220 Thr Ser Ser Phe Phe Ile Arg Asp Ile IleLys Pro Asp Pro Pro Thr 225 230 235 240 Asn Leu Gln Leu Lys Pro Leu LysAsn Ser Arg His Val Glu Val Ser 245 250 255 Trp Glu Tyr Pro Asp Thr TrpSer Thr Pro His Ser Tyr Phe Ser Leu 260 265 270 Thr Phe Cys Ile Gln AlaGln Gly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285 Arg Leu Cys Val AspLys Thr Ser Ala Lys Val Val Cys His Lys Asp 290 295 300 Ala Lys Ile ArgVal Gln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 Ser AspTrp Ala Ser Val Ser Cys Ser Gly Gly Gly Gly Gly Gly Ser 325 330 335 ArgAsn Leu Pro Thr Pro Thr Pro Ser Pro Gly Met Phe Gln Cys Leu 340 345 350Asn His Ser Gln Thr Leu Leu Arg Ala Val Ser Asn Thr Leu Gln Lys 355 360365 Ala Arg Gln Thr Leu Glu Leu Tyr Ser Cys Thr Ser Glu Glu Ile Asp 370375 380 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu385 390 395 400 Pro Leu Glu Leu Thr Met Asn Glu Ser Cys Leu Ala Ser ArgGlu Ile 405 410 415 Ser Leu Ile Thr Asn Gly Ser Cys Leu Ala Ser Gly LysAla Ser Phe 420 425 430 Met Thr Val Leu Cys Leu Ser Ser Ile Tyr Glu AspLeu Lys Met Tyr 435 440 445 Gln Met Glu Phe Lys Ala Met Asn Ala Lys LeuLeu Met Asp Pro Lys 450 455 460 Arg Gln Ile Phe Leu Asp Gln Asn Met LeuThr Ala Ile Asp Glu Leu 465 470 475 480 Leu Gln Ala Leu Asn Phe Asn SerVal Thr Val Pro Gln Lys Ser Ser 485 490 495 Leu Glu Glu Pro Asp Phe TyrLys Thr Lys Ile Lys Leu Cys Ile Leu 500 505 510 Leu His Ala Phe Arg IleArg Ala Val Thr Ile Asn Arg Met Met Ser 515 520 525 Tyr Leu Asn Ser Ser530 63 1599 DNA Canis familiaris 63 ggaagagttc aagtaggaca tcattctattgatggtcacc gcacgaattc tgaaagcatg 60 aagaagtatg cagagcttga ttttagttttataaaaatcc ggctcttcaa gggaggattt 120 ctgtggcaca gtcacactgt tgaaattcagggcctgtaac agctcatcga tagctgtcag 180 catgttttga tccagaaaga tctgcctcttgggatccatt aaaagctttg cgttcatggc 240 cttgaattcc atctggtaca tcttcaagtcctcatagatg ctgctaaggc acaggaccgt 300 cataaaagag gcctttccag aggccaggcaactcccgtta gttatcaaag agatctctct 360 ggaagccagg caactctcat tcatggttaattccagtggt aagcaggcct ccactgtgct 420 ggttttatcc tttgtgatat cttcatgatcaatctcttcg gaagtgcagg aatataattc 480 tagagtttgt ctggccttct gaagcgtgttgctgacggct ctcaacaagg tttgggagtg 540 gttcaaacat tggaacatac ccggggatggagtaggggtt ggcaagtttc tagatccgcc 600 gccaccgcca ccactgcatg acacagatgcccagtcgctc caggatgaac tatagtagcg 660 gtctcgggct tgcacgcgga tcttggcatccttgtggcac acgaccttgg ctgaggtctt 720 gtccacgcag agtctatctt tcttttctctattgttcttg ccctgggcct gtatgcaaaa 780 tgtcagggag aagtaggaat gtggggtgctccaggtgtcg gggtattccc agctgacctc 840 cacgtgccga gaatttttca atggcttcagctgcaggttt gtgggtgggt ctggtttgat 900 gatgtctctg atgaagaagc tgctggtgtagttttcatac ttgagcttgt gaatagcatc 960 caccacgacc tcgatgggta ggctctcctcggcagagggg caggcactgc cctcctgaca 1020 ctccactgtg tacttcttat aatccctgttgtccactctg accctctctg ctgaaagtgt 1080 cactgctcca catgtcaccc cttgggggtcagagaagcct ctgctacttt tgacactgaa 1140 tttcaaatca gtactgattg ccgtcagccaccagcatgtg aaacgtccag aataattctt 1200 tgcctcacat ttcagaaaga tcttatttttggattctttc tgttccttta agatatcagt 1260 ggaccaaatt ccatcttctt ttttgtgaatcaacaggagt gagcggctca gaaccttgcc 1320 tcctttatgg caggtatact ggccagcatctccaaattct ttgacttgga tggtcagagt 1380 tttaccagaa cctaggactt cactgctctgcgctgaggtc caagtgatgt catcttcttc 1440 aggggtatgg caggtgagga ccaccatttctccgggggca tcagggtgcc agtccaactc 1500 tacaacataa acatctttct ccagttcccatatggccatg aggggagacg ccagcaaaac 1560 gagggaaaac caggagatga ccaactgctgagggtgcat 1599 64 0 DNA Canis familiaris 64 000 65 0 DNA Canisfamiliaris 65 000 66 1533 DNA Canis familiaris CDS (1)..(1533) 66 atatgg gaa ctg gag aaa gat gtt tat gtt gta gag ttg gac tgg cac 48 Ile TrpGlu Leu Glu Lys Asp Val Tyr Val Val Glu Leu Asp Trp His 1 5 10 15 cctgat gcc ccc gga gaa atg gtg gtc ctc acc tgc cat acc cct gaa 96 Pro AspAla Pro Gly Glu Met Val Val Leu Thr Cys His Thr Pro Glu 20 25 30 gaa gatgac atc act tgg acc tca gcg cag agc agt gaa gtc cta ggt 144 Glu Asp AspIle Thr Trp Thr Ser Ala Gln Ser Ser Glu Val Leu Gly 35 40 45 tct ggt aaaact ctg acc atc caa gtc aaa gaa ttt gga gat gct ggc 192 Ser Gly Lys ThrLeu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 cag tat acc tgccat aaa gga ggc aag gtt ctg agc cgc tca ctc ctg 240 Gln Tyr Thr Cys HisLys Gly Gly Lys Val Leu Ser Arg Ser Leu Leu 65 70 75 80 ttg att cac aaaaaa gaa gat gga att tgg tcc act gat atc tta aag 288 Leu Ile His Lys LysGlu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 gaa cag aaa gaa tccaaa aat aag atc ttt ctg aaa tgt gag gca aag 336 Glu Gln Lys Glu Ser LysAsn Lys Ile Phe Leu Lys Cys Glu Ala Lys 100 105 110 aat tat tct gga cgtttc aca tgc tgg tgg ctg acg gca atc agt act 384 Asn Tyr Ser Gly Arg PheThr Cys Trp Trp Leu Thr Ala Ile Ser Thr 115 120 125 gat ttg aaa ttc agtgtc aaa agt agc aga ggc ttc tct gac ccc caa 432 Asp Leu Lys Phe Ser ValLys Ser Ser Arg Gly Phe Ser Asp Pro Gln 130 135 140 ggg gtg aca tgt ggagca gtg aca ctt tca gca gag agg gtc aga gtg 480 Gly Val Thr Cys Gly AlaVal Thr Leu Ser Ala Glu Arg Val Arg Val 145 150 155 160 gac aac agg gattat aag aag tac aca gtg gag tgt cag gag ggc agt 528 Asp Asn Arg Asp TyrLys Lys Tyr Thr Val Glu Cys Gln Glu Gly Ser 165 170 175 gcc tgc ccc tctgcc gag gag agc cta ccc atc gag gtc gtg gtg gat 576 Ala Cys Pro Ser AlaGlu Glu Ser Leu Pro Ile Glu Val Val Val Asp 180 185 190 gct att cac aagctc aag tat gaa aac tac acc agc agc ttc ttc atc 624 Ala Ile His Lys LeuLys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile 195 200 205 aga gac atc atcaaa cca gac cca ccc aca aac ctg cag ctg aag cca 672 Arg Asp Ile Ile LysPro Asp Pro Pro Thr Asn Leu Gln Leu Lys Pro 210 215 220 ttg aaa aat tctcgg cac gtg gag gtc agc tgg gaa tac ccc gac acc 720 Leu Lys Asn Ser ArgHis Val Glu Val Ser Trp Glu Tyr Pro Asp Thr 225 230 235 240 tgg agc acccca cat tcc tac ttc tcc ctg aca ttt tgc ata cag gcc 768 Trp Ser Thr ProHis Ser Tyr Phe Ser Leu Thr Phe Cys Ile Gln Ala 245 250 255 cag ggc aagaac aat aga gaa aag aaa gat aga ctc tgc gtg gac aag 816 Gln Gly Lys AsnAsn Arg Glu Lys Lys Asp Arg Leu Cys Val Asp Lys 260 265 270 acc tca gccaag gtc gtg tgc cac aag gat gcc aag atc cgc gtg caa 864 Thr Ser Ala LysVal Val Cys His Lys Asp Ala Lys Ile Arg Val Gln 275 280 285 gcc cga gaccgc tac tat agt tca tcc tgg agc gac tgg gca tct gtg 912 Ala Arg Asp ArgTyr Tyr Ser Ser Ser Trp Ser Asp Trp Ala Ser Val 290 295 300 tca tgc agtggt ggc ggt ggc ggc gga tct aga aac ttg cca acc cct 960 Ser Cys Ser GlyGly Gly Gly Gly Gly Ser Arg Asn Leu Pro Thr Pro 305 310 315 320 act ccatcc ccg ggt atg ttc caa tgt ttg aac cac tcc caa acc ttg 1008 Thr Pro SerPro Gly Met Phe Gln Cys Leu Asn His Ser Gln Thr Leu 325 330 335 ttg agagcc gtc agc aac acg ctt cag aag gcc aga caa act cta gaa 1056 Leu Arg AlaVal Ser Asn Thr Leu Gln Lys Ala Arg Gln Thr Leu Glu 340 345 350 tta tattcc tgc act tcc gaa gag att gat cat gaa gat atc aca aag 1104 Leu Tyr SerCys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys 355 360 365 gat aaaacc agc aca gtg gag gcc tgc tta cca ctg gaa tta acc atg 1152 Asp Lys ThrSer Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Met 370 375 380 aat gagagt tgc ctg gct tcc aga gag atc tct ttg ata act aac ggg 1200 Asn Glu SerCys Leu Ala Ser Arg Glu Ile Ser Leu Ile Thr Asn Gly 385 390 395 400 agttgc ctg gcc tct gga aag gcc tct ttt atg acg gtc ctg tgc ctt 1248 Ser CysLeu Ala Ser Gly Lys Ala Ser Phe Met Thr Val Leu Cys Leu 405 410 415 agcagc atc tat gag gac ttg aag atg tac cag atg gaa ttc aag gcc 1296 Ser SerIle Tyr Glu Asp Leu Lys Met Tyr Gln Met Glu Phe Lys Ala 420 425 430 atgaac gca aag ctt tta atg gat ccc aag agg cag atc ttt ctg gat 1344 Met AsnAla Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp 435 440 445 caaaac atg ctg aca gct atc gat gag ctg tta cag gcc ctg aat ttc 1392 Gln AsnMet Leu Thr Ala Ile Asp Glu Leu Leu Gln Ala Leu Asn Phe 450 455 460 aacagt gtg act gtg cca cag aaa tcc tcc ctt gaa gag ccg gat ttt 1440 Asn SerVal Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe 465 470 475 480tat aaa act aaa atc aag ctc tgc ata ctt ctt cat gct ttc aga att 1488 TyrLys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile 485 490 495cgt gcg gtg acc atc aat aga atg atg tcc tac ttg aac tct tcc 1533 Arg AlaVal Thr Ile Asn Arg Met Met Ser Tyr Leu Asn Ser Ser 500 505 510 67 511PRT Canis familiaris 67 Ile Trp Glu Leu Glu Lys Asp Val Tyr Val Val GluLeu Asp Trp His 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu ThrCys His Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Ala Gln SerSer Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys GluPhe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Lys Val LeuSer Arg Ser Leu Leu 65 70 75 80 Leu Ile His Lys Lys Glu Asp Gly Ile TrpSer Thr Asp Ile Leu Lys 85 90 95 Glu Gln Lys Glu Ser Lys Asn Lys Ile PheLeu Lys Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys TrpTrp Leu Thr Ala Ile Ser Thr 115 120 125 Asp Leu Lys Phe Ser Val Lys SerSer Arg Gly Phe Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala ValThr Leu Ser Ala Glu Arg Val Arg Val 145 150 155 160 Asp Asn Arg Asp TyrLys Lys Tyr Thr Val Glu Cys Gln Glu Gly Ser 165 170 175 Ala Cys Pro SerAla Glu Glu Ser Leu Pro Ile Glu Val Val Val Asp 180 185 190 Ala Ile HisLys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile 195 200 205 Arg AspIle Ile Lys Pro Asp Pro Pro Thr Asn Leu Gln Leu Lys Pro 210 215 220 LeuLys Asn Ser Arg His Val Glu Val Ser Trp Glu Tyr Pro Asp Thr 225 230 235240 Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Ile Gln Ala 245250 255 Gln Gly Lys Asn Asn Arg Glu Lys Lys Asp Arg Leu Cys Val Asp Lys260 265 270 Thr Ser Ala Lys Val Val Cys His Lys Asp Ala Lys Ile Arg ValGln 275 280 285 Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Asp Trp AlaSer Val 290 295 300 Ser Cys Ser Gly Gly Gly Gly Gly Gly Ser Arg Asn LeuPro Thr Pro 305 310 315 320 Thr Pro Ser Pro Gly Met Phe Gln Cys Leu AsnHis Ser Gln Thr Leu 325 330 335 Leu Arg Ala Val Ser Asn Thr Leu Gln LysAla Arg Gln Thr Leu Glu 340 345 350 Leu Tyr Ser Cys Thr Ser Glu Glu IleAsp His Glu Asp Ile Thr Lys 355 360 365 Asp Lys Thr Ser Thr Val Glu AlaCys Leu Pro Leu Glu Leu Thr Met 370 375 380 Asn Glu Ser Cys Leu Ala SerArg Glu Ile Ser Leu Ile Thr Asn Gly 385 390 395 400 Ser Cys Leu Ala SerGly Lys Ala Ser Phe Met Thr Val Leu Cys Leu 405 410 415 Ser Ser Ile TyrGlu Asp Leu Lys Met Tyr Gln Met Glu Phe Lys Ala 420 425 430 Met Asn AlaLys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp 435 440 445 Gln AsnMet Leu Thr Ala Ile Asp Glu Leu Leu Gln Ala Leu Asn Phe 450 455 460 AsnSer Val Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe 465 470 475480 Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile 485490 495 Arg Ala Val Thr Ile Asn Arg Met Met Ser Tyr Leu Asn Ser Ser 500505 510 68 1533 DNA Canis familiaris 68 ggaagagttc aagtaggaca tcattctattgatggtcacc gcacgaattc tgaaagcatg 60 aagaagtatg cagagcttga ttttagttttataaaaatcc ggctcttcaa gggaggattt 120 ctgtggcaca gtcacactgt tgaaattcagggcctgtaac agctcatcga tagctgtcag 180 catgttttga tccagaaaga tctgcctcttgggatccatt aaaagctttg cgttcatggc 240 cttgaattcc atctggtaca tcttcaagtcctcatagatg ctgctaaggc acaggaccgt 300 cataaaagag gcctttccag aggccaggcaactcccgtta gttatcaaag agatctctct 360 ggaagccagg caactctcat tcatggttaattccagtggt aagcaggcct ccactgtgct 420 ggttttatcc tttgtgatat cttcatgatcaatctcttcg gaagtgcagg aatataattc 480 tagagtttgt ctggccttct gaagcgtgttgctgacggct ctcaacaagg tttgggagtg 540 gttcaaacat tggaacatac ccggggatggagtaggggtt ggcaagtttc tagatccgcc 600 gccaccgcca ccactgcatg acacagatgcccagtcgctc caggatgaac tatagtagcg 660 gtctcgggct tgcacgcgga tcttggcatccttgtggcac acgaccttgg ctgaggtctt 720 gtccacgcag agtctatctt tcttttctctattgttcttg ccctgggcct gtatgcaaaa 780 tgtcagggag aagtaggaat gtggggtgctccaggtgtcg gggtattccc agctgacctc 840 cacgtgccga gaatttttca atggcttcagctgcaggttt gtgggtgggt ctggtttgat 900 gatgtctctg atgaagaagc tgctggtgtagttttcatac ttgagcttgt gaatagcatc 960 caccacgacc tcgatgggta ggctctcctcggcagagggg caggcactgc cctcctgaca 1020 ctccactgtg tacttcttat aatccctgttgtccactctg accctctctg ctgaaagtgt 1080 cactgctcca catgtcaccc cttgggggtcagagaagcct ctgctacttt tgacactgaa 1140 tttcaaatca gtactgattg ccgtcagccaccagcatgtg aaacgtccag aataattctt 1200 tgcctcacat ttcagaaaga tcttatttttggattctttc tgttccttta agatatcagt 1260 ggaccaaatt ccatcttctt ttttgtgaatcaacaggagt gagcggctca gaaccttgcc 1320 tcctttatgg caggtatact ggccagcatctccaaattct ttgacttgga tggtcagagt 1380 tttaccagaa cctaggactt cactgctctgcgctgaggtc caagtgatgt catcttcttc 1440 aggggtatgg caggtgagga ccaccatttctccgggggca tcagggtgcc agtccaactc 1500 tacaacataa acatctttct ccagttcccatat 1533 69 30 DNA Artificial sequence Synthetic Primer 69 gccaagctcgaaattaaccc tcactaaagg 30 70 28 DNA Artificial sequence Synthetic Primer70 cgacggccag tgaattgtaa tacgactc 28 71 31 DNA Artificial sequenceSynthetic Primer 71 agtgatgaag gcctggaatc agattacttt g 31 72 32 DNAArtificial sequence Synthetic Primer 72 atggcctgga acacttctct gaaagaatatga 32 73 30 DNA Artificial sequence Synthetic Primer 73 aactattgagcacagggata aagatgactg 30 74 33 DNA Artificial sequence Synthetic Primer74 aatatctaat tcttgttttg aacagtgaac att 33 75 36 DNA Artificial sequenceSynthetic Primer 75 tatgccggct actttggcaa gcttgaacat aaactc 36 76 37 DNAArtificial sequence Synthetic Primer 76 ggcctcgagc taattcttgt tttgaacagtgaacatt 37 77 28 DNA Artificial sequence Synthetic Primer 77 atggccgacaaggtcctgaa ggagaaga 28 78 33 DNA Artificial sequence Synthetic Primer 78ttaatgtcct gggaagaggt agaaacatct tgt 33 79 26 DNA Artificial sequenceSynthetic Primer 79 tcaagcccac aatctggaaa ttctca 26 80 26 DNA Artificialsequence Synthetic Primer 80 ctggagagtc actgatcaac agttcc 26 81 36 DNAArtificial sequence Synthetic Primer 81 acaaggatcc accatggccg acaaggatctgaaggg 36 82 39 DNA Artificial sequence Synthetic Primer 82 cgcctctagacctcaattgc cagggaagag atagaagta 39 83 60 DNA Artificial sequenceSynthetic Primer 83 ctgcagtggt ggcggtggcg gcggatctag aaacttgccaacccctactc catccccggg 60 84 60 DNA Artificial sequence Synthetic Primer84 cccggggatg gagtaggggt tggcaagttt ctagatccgc cgccaccgcc accactgcag 6085 28 DNA Artificial sequence Synthetic Primer 85 atgcatcctc agcagttggtcatcgcct 28 86 25 DNA Artificial sequence Synthetic Primer 86 tgcaggacacggatgcccag ttgct 25 87 37 DNA Artificial sequence Synthetic Primer 87acaggtacca tgcatcctca gcagttggtc atcgcct 37 88 25 DNA Artificialsequence Synthetic Primer 88 ctaactgcag gacacggatg cccag 25 89 19 DNAArtificial sequence Synthetic Primer 89 atgtgcccgc cgcgtggcc 19 90 27DNA Artificial sequence Synthetic Primer 90 ctaggaagca ttcagatagctcatcat 27 91 39 DNA Artificial sequence Synthetic Primer 91 tatgacccggggatgttcca gtgcctcaac cactcccaa 39 92 41 DNA Artificial sequenceSynthetic Primer 92 atgactgcgg ccgcctagga agcattcaga tagctcatca t 41 9320 DNA Artificial sequence Synthetic Primer 93 ccatcctggt cctgctaagc 2094 22 DNA Artificial sequence Synthetic Primer 94 ccatctggta catcttcaagtc 22 95 38 DNA Artificial sequence Synthetic Primer 95 aaaaaacccgggtatgttcc aatgtttcaa ccactccc 38 96 51 DNA Artificial sequenceSynthetic Primer 96 gcggccgctc gagttaggaa gagttcaagt aggacatcattctattgatg g 51 97 22 DNA Artificial sequence Synthetic Primer 97cttaaaggaa cagaaagaat cc 22 98 19 DNA Artificial sequence SyntheticPrimer 98 ggtattccca gctgacctc 19 99 37 DNA Artificial sequenceSynthetic Primer 99 cataggtacc atgcaccctc agcagttggt catctcc 37 100 29DNA Artificial sequence Synthetic Primer 100 atctaaatgc atgacacagatgcccagtc 29 101 561 DNA Felis catus CDS (1)..(561) 101 ggg atg ttc cagtgc ctc aac cac tcc caa acc ctg ctg cga gcc atc 48 Gly Met Phe Gln CysLeu Asn His Ser Gln Thr Leu Leu Arg Ala Ile 1 5 10 15 agc aac acg cttcag aag gcc aga caa act cta gaa ttt tac tcc tgc 96 Ser Asn Thr Leu GlnLys Ala Arg Gln Thr Leu Glu Phe Tyr Ser Cys 20 25 30 act tcc gaa gag attgat cat gaa gat atc aca aaa gat aaa acc agc 144 Thr Ser Glu Glu Ile AspHis Glu Asp Ile Thr Lys Asp Lys Thr Ser 35 40 45 aca gtg gag gcc tgc ttacca ctg gaa tta acc atg aat gag agt tgc 192 Thr Val Glu Ala Cys Leu ProLeu Glu Leu Thr Met Asn Glu Ser Cys 50 55 60 ctg gct tcc aga gag atc tctctg ata act aat ggg agt tgc ctg gcc 240 Leu Ala Ser Arg Glu Ile Ser LeuIle Thr Asn Gly Ser Cys Leu Ala 65 70 75 80 tcc aga aag acc tct ttt atgacg acc ctg tgc ctt agc agt atc tat 288 Ser Arg Lys Thr Ser Phe Met ThrThr Leu Cys Leu Ser Ser Ile Tyr 85 90 95 gag gac ttg aag atg tac cag gtggag ttc aag gcc atg aat gca aag 336 Glu Asp Leu Lys Met Tyr Gln Val GluPhe Lys Ala Met Asn Ala Lys 100 105 110 ctg tta atg gat cct aaa agg cagatc ttt ctg gat caa aac atg ctg 384 Leu Leu Met Asp Pro Lys Arg Gln IlePhe Leu Asp Gln Asn Met Leu 115 120 125 aca gct att gat gag ctg tta caggcc ctg aat gtc aac agt gtg act 432 Thr Ala Ile Asp Glu Leu Leu Gln AlaLeu Asn Val Asn Ser Val Thr 130 135 140 gtg cca cag aac tcc tcc ctg gaagaa ccg gat ttt tat aaa act aaa 480 Val Pro Gln Asn Ser Ser Leu Glu GluPro Asp Phe Tyr Lys Thr Lys 145 150 155 160 atc aag ctc tgc ata ctt cttcat gct ttc aga att cgt gca gtg acc 528 Ile Lys Leu Cys Ile Leu Leu HisAla Phe Arg Ile Arg Ala Val Thr 165 170 175 atc aat aga atg atg agc tatctg aat gct tcc 561 Ile Asn Arg Met Met Ser Tyr Leu Asn Ala Ser 180 185102 187 PRT Felis catus 102 Gly Met Phe Gln Cys Leu Asn His Ser Gln ThrLeu Leu Arg Ala Ile 1 5 10 15 Ser Asn Thr Leu Gln Lys Ala Arg Gln ThrLeu Glu Phe Tyr Ser Cys 20 25 30 Thr Ser Glu Glu Ile Asp His Glu Asp IleThr Lys Asp Lys Thr Ser 35 40 45 Thr Val Glu Ala Cys Leu Pro Leu Glu LeuThr Met Asn Glu Ser Cys 50 55 60 Leu Ala Ser Arg Glu Ile Ser Leu Ile ThrAsn Gly Ser Cys Leu Ala 65 70 75 80 Ser Arg Lys Thr Ser Phe Met Thr ThrLeu Cys Leu Ser Ser Ile Tyr 85 90 95 Glu Asp Leu Lys Met Tyr Gln Val GluPhe Lys Ala Met Asn Ala Lys 100 105 110 Leu Leu Met Asp Pro Lys Arg GlnIle Phe Leu Asp Gln Asn Met Leu 115 120 125 Thr Ala Ile Asp Glu Leu LeuGln Ala Leu Asn Val Asn Ser Val Thr 130 135 140 Val Pro Gln Asn Ser SerLeu Glu Glu Pro Asp Phe Tyr Lys Thr Lys 145 150 155 160 Ile Lys Leu CysIle Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr 165 170 175 Ile Asn ArgMet Met Ser Tyr Leu Asn Ala Ser 180 185 103 561 DNA Felis catus 103ggaagcattc agatagctca tcattctatt gatggtcact gcacgaattc tgaaagcatg 60aagaagtatg cagagcttga ttttagtttt ataaaaatcc ggttcttcca gggaggagtt 120ctgtggcaca gtcacactgt tgacattcag ggcctgtaac agctcatcaa tagctgtcag 180catgttttga tccagaaaga tctgcctttt aggatccatt aacagctttg cattcatggc 240cttgaactcc acctggtaca tcttcaagtc ctcatagata ctgctaaggc acagggtcgt 300cataaaagag gtctttctgg aggccaggca actcccatta gttatcagag agatctctct 360ggaagccagg caactctcat tcatggttaa ttccagtggt aagcaggcct ccactgtgct 420ggttttatct tttgtgatat cttcatgatc aatctcttcg gaagtgcagg agtaaaattc 480tagagtttgt ctggccttct gaagcgtgtt gctgatggct cgcagcaggg tttgggagtg 540gttgaggcac tggaacatcc c 561 104 1455 DNA Canis familiaris CDS(232)..(897) 104 ggcacgaggc aaaccccgcg ggcccagctc cacgtgtcac cgagaagctgatgtagagag 60 agacagagag agaaagcaag ccggacaccg gagtcccggg aaagtcctggcgcgcctcgg 120 gccaattata aaaatgtgac cccccgggtc ggcctcccac cgccgccctcccctgccgcg 180 tccgcagtcc gcgtccagcg cccgccgggg tccacgcagc gcccgcccag catg tgc 237 Met Cys 1 ccg ccg cgc ggc ctc ctc ctt gtg acc atc ctg gtcctg cta agc cac 285 Pro Pro Arg Gly Leu Leu Leu Val Thr Ile Leu Val LeuLeu Ser His 5 10 15 ctg gac cac ctt act tgg gcc agg agc ctc ccc aca gcctca ccg agc 333 Leu Asp His Leu Thr Trp Ala Arg Ser Leu Pro Thr Ala SerPro Ser 20 25 30 cca gga ata ttc cag tgc ctc aac cac tcc caa aac ctg ctgaga gcc 381 Pro Gly Ile Phe Gln Cys Leu Asn His Ser Gln Asn Leu Leu ArgAla 35 40 45 50 gtc agc aac acg ctt cag aag gcc aga caa act cta gaa ttatat tcc 429 Val Ser Asn Thr Leu Gln Lys Ala Arg Gln Thr Leu Glu Leu TyrSer 55 60 65 tgc act tcc gaa gag att gat cat gaa gat atc aca aag gat aaaacc 477 Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr70 75 80 agc aca gtg gag gcc tgc tta cca ctg gaa tta acc atg aat gag agt525 Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Met Asn Glu Ser 8590 95 tgc ctg gct tcc aga gag atc tct ttg ata act aac ggg agt tgc ctg573 Cys Leu Ala Ser Arg Glu Ile Ser Leu Ile Thr Asn Gly Ser Cys Leu 100105 110 gcc tct gga aag gcc tct ttt atg acg gtc ctg tgc ctt agc agc atc621 Ala Ser Gly Lys Ala Ser Phe Met Thr Val Leu Cys Leu Ser Ser Ile 115120 125 130 tat gag gac ttg aag atg tac cag atg gaa ttc aag gcc atg aacgca 669 Tyr Glu Asp Leu Lys Met Tyr Gln Met Glu Phe Lys Ala Met Asn Ala135 140 145 aag ctt tta atg gat ccc aag agg cag atc ttt ctg gat caa aacatg 717 Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met150 155 160 ctg aca gct atc gat gag ctg tta cag gcc ctg aat ttc aac agtgtg 765 Leu Thr Ala Ile Asp Glu Leu Leu Gln Ala Leu Asn Phe Asn Ser Val165 170 175 act gtg cca cag aaa tcc tcc ctt gaa gag ccg gat ttt tat aaaact 813 Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr180 185 190 aaa atc aag ctc tgc ata ctt ctt cat gct ttc aga att cgt gcggtg 861 Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val195 200 205 210 acc atc gat aga atg atg agt tat ctg aat tct tcctaaaaagctg 907 Thr Ile Asp Arg Met Met Ser Tyr Leu Asn Ser Ser 215 220aggtctctct cgactttaaa gtcattccta taaaaatgtg aacccaaaag aatttttcat 967aagatagggg ttaagaacca gggagggggt ggcttgacct ggtcctactt aagctagtac 1027gataattctc atgcttgttt acattagttg ccactcaaat tttgaaagat gtgactgtta 1087tatcccacac gatgcctttg accaagtata tttcacattt actatggata agttaagtgt 1147tcgtgagcaa attgctaaag aggaaaaatg tcctcaccga acatgttttt attttccctt 1207taatagaaga gcaagacttt ataagctatt tctgtaccaa actgtttgta gaaacaaaca 1267ctcaagcata atttatttaa aaatacttat ttatataatt ttgtgttcat gaaagcatgt 1327gaattaattt atatttattt atgttatatt tattaaagta tttattatca agtggatttg 1387ggatatctta tgttctaaaa ataaaatgat tgagtagaaa aaaaaaaaaa aaaaaaaaaa 1447aaaaaaaa 1455 105 222 PRT Canis familiaris 105 Met Cys Pro Pro Arg GlyLeu Leu Leu Val Thr Ile Leu Val Leu Leu 1 5 10 15 Ser His Leu Asp HisLeu Thr Trp Ala Arg Ser Leu Pro Thr Ala Ser 20 25 30 Pro Ser Pro Gly IlePhe Gln Cys Leu Asn His Ser Gln Asn Leu Leu 35 40 45 Arg Ala Val Ser AsnThr Leu Gln Lys Ala Arg Gln Thr Leu Glu Leu 50 55 60 Tyr Ser Cys Thr SerGlu Glu Ile Asp His Glu Asp Ile Thr Lys Asp 65 70 75 80 Lys Thr Ser ThrVal Glu Ala Cys Leu Pro Leu Glu Leu Thr Met Asn 85 90 95 Glu Ser Cys LeuAla Ser Arg Glu Ile Ser Leu Ile Thr Asn Gly Ser 100 105 110 Cys Leu AlaSer Gly Lys Ala Ser Phe Met Thr Val Leu Cys Leu Ser 115 120 125 Ser IleTyr Glu Asp Leu Lys Met Tyr Gln Met Glu Phe Lys Ala Met 130 135 140 AsnAla Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln 145 150 155160 Asn Met Leu Thr Ala Ile Asp Glu Leu Leu Gln Ala Leu Asn Phe Asn 165170 175 Ser Val Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr180 185 190 Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg IleArg 195 200 205 Ala Val Thr Ile Asp Arg Met Met Ser Tyr Leu Asn Ser Ser210 215 220 106 1455 DNA Canis familiaris 106 tttttttttt tttttttttttttttttttt tctactcaat cattttattt ttagaacata 60 agatatccca aatccacttgataataaata ctttaataaa tataacataa ataaatataa 120 attaattcac atgctttcatgaacacaaaa ttatataaat aagtattttt aaataaatta 180 tgcttgagtg tttgtttctacaaacagttt ggtacagaaa tagcttataa agtcttgctc 240 ttctattaaa gggaaaataaaaacatgttc ggtgaggaca tttttcctct ttagcaattt 300 gctcacgaac acttaacttatccatagtaa atgtgaaata tacttggtca aaggcatcgt 360 gtgggatata acagtcacatctttcaaaat ttgagtggca actaatgtaa acaagcatga 420 gaattatcgt actagcttaagtaggaccag gtcaagccac cccctccctg gttcttaacc 480 cctatcttat gaaaaattcttttgggttca catttttata ggaatgactt taaagtcgag 540 agagacctca gctttttaggaagaattcag ataactcatc attctatcga tggtcaccgc 600 acgaattctg aaagcatgaagaagtatgca gagcttgatt ttagttttat aaaaatccgg 660 ctcttcaagg gaggatttctgtggcacagt cacactgttg aaattcaggg cctgtaacag 720 ctcatcgata gctgtcagcatgttttgatc cagaaagatc tgcctcttgg gatccattaa 780 aagctttgcg ttcatggccttgaattccat ctggtacatc ttcaagtcct catagatgct 840 gctaaggcac aggaccgtcataaaagaggc ctttccagag gccaggcaac tcccgttagt 900 tatcaaagag atctctctggaagccaggca actctcattc atggttaatt ccagtggtaa 960 gcaggcctcc actgtgctggttttatcctt tgtgatatct tcatgatcaa tctcttcgga 1020 agtgcaggaa tataattctagagtttgtct ggccttctga agcgtgttgc tgacggctct 1080 cagcaggttt tgggagtggttgaggcactg gaatattcct gggctcggtg aggctgtggg 1140 gaggctcctg gcccaagtaaggtggtccag gtggcttagc aggaccagga tggtcacaag 1200 gaggaggccg cgcggcgggcacatgctggg cgggcgctgc gtggaccccg gcgggcgctg 1260 gacgcggact gcggacgcggcaggggaggg cggcggtggg aggccgaccc ggggggtcac 1320 atttttataa ttggcccgaggcgcgccagg actttcccgg gactccggtg tccggcttgc 1380 tttctctctc tgtctctctctacatcagct tctcggtgac acgtggagct gggcccgcgg 1440 ggtttgcctc gtgcc 1455107 2267 DNA Canis familiaris CDS (154)..(1140) 107 ggcacgaggcaacttggaca agtcagtttc tagtttaagt ttccatccaa aagctcggta 60 ggagtagggtatataagctc cagtagcagt agcagcagca gcaggagact ccgtttcaga 120 cccagggaaccttgcagcct ggccagaagc aag atg cat cct cag cag ttg gtc 174 Met His ProGln Gln Leu Val 1 5 atc tcc tgg ttt tcc ctc gtt ttg ctg gcg tct ccc ctcatg gcc ata 222 Ile Ser Trp Phe Ser Leu Val Leu Leu Ala Ser Pro Leu MetAla Ile 10 15 20 tgg gaa ctg gag aaa gat gtt tat gtt gta gag ttg gac tggcac cct 270 Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Leu Asp Trp HisPro 25 30 35 gat gcc ccc gga gaa atg gtg gtc ctc acc tgc cat acc cct gaagaa 318 Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys His Thr Pro Glu Glu40 45 50 55 gat gac atc act tgg acc tca gcg cag agc agt gaa gtc cta ggttct 366 Asp Asp Ile Thr Trp Thr Ser Ala Gln Ser Ser Glu Val Leu Gly Ser60 65 70 ggt aaa act ctg acc atc caa gtc aaa gaa ttt gga gat gct ggc cag414 Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly Gln 7580 85 tat acc tgc cat aaa gga ggc aag gtt ctg agc cgc tca ctc ctg ttg462 Tyr Thr Cys His Lys Gly Gly Lys Val Leu Ser Arg Ser Leu Leu Leu 9095 100 att cac aaa aaa gaa gat gga att tgg tcc act gat atc tta aag gaa510 Ile His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys Glu 105110 115 cag aaa gaa tcc aaa aat aag atc ttt ctg aaa tgt gag gca aag aat558 Gln Lys Glu Ser Lys Asn Lys Ile Phe Leu Lys Cys Glu Ala Lys Asn 120125 130 135 tat tct gga cgt ttc aca tgc tgg tgg ctg acg gca atc agt actgat 606 Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Ala Ile Ser Thr Asp140 145 150 ttg aaa ttc agt gtc aaa agt agc aga ggc ttc tct gac ccc caaggg 654 Leu Lys Phe Ser Val Lys Ser Ser Arg Gly Phe Ser Asp Pro Gln Gly155 160 165 gtg aca tgt gga gca gtg aca ctt tca gca gag agg gtc aga gtggac 702 Val Thr Cys Gly Ala Val Thr Leu Ser Ala Glu Arg Val Arg Val Asp170 175 180 aac agg gat tat aag aag tac aca gtg gag tgt cag gag ggc agtgcc 750 Asn Arg Asp Tyr Lys Lys Tyr Thr Val Glu Cys Gln Glu Gly Ser Ala185 190 195 tgc ccc tct gcc gag gag agc cta ccc atc gag gtc gtg gtg gatgct 798 Cys Pro Ser Ala Glu Glu Ser Leu Pro Ile Glu Val Val Val Asp Ala200 205 210 215 att cac aag ctc aag tat gaa aac tac acc agc agc ttc ttcatc aga 846 Ile His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe IleArg 220 225 230 gac atc atc aaa cca gac cca ccc aca aac ctg cag ctg aagcca ttg 894 Asp Ile Ile Lys Pro Asp Pro Pro Thr Asn Leu Gln Leu Lys ProLeu 235 240 245 aaa aat tct cgg cac gtg gag gtc agc tgg gaa tac ccc gacacc tgg 942 Lys Asn Ser Arg His Val Glu Val Ser Trp Glu Tyr Pro Asp ThrTrp 250 255 260 agc acc cca cat tcc tac ttc tcc ctg aca ttt tgc ata caggcc cag 990 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Ile Gln AlaGln 265 270 275 ggc aag aac aat aga gaa aag aaa gat aga ctc tgc gtg gacaag acc 1038 Gly Lys Asn Asn Arg Glu Lys Lys Asp Arg Leu Cys Val Asp LysThr 280 285 290 295 tca gcc aag gtc gtg tgc cac aag gat gcc aag atc cgcgtg caa gcc 1086 Ser Ala Lys Val Val Cys His Lys Asp Ala Lys Ile Arg ValGln Ala 300 305 310 cga gac cgc tac tat agt tca tcc tgg agc gac tgg gcatct gtg tcc 1134 Arg Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Asp Trp Ala SerVal Ser 315 320 325 tgc agt taggttccac ccccaggatg aatcttggag ggaaagtggaagatattatg 1190 Cys Ser caaaattttc taaggacaca ttgaagaggc tccaaaagttattttctgcc taattttctt 1250 tttgtaaagg gtcattattg tgtcttcgca atattttttacatttaaatg ccaaatgccc 1310 actgaaacaa tcagctactt tatttataga ttttcagctagcaggctgcc actgacctta 1370 atgctattta aatatttaag taatttatgt atttattaatttattgttat tgaacacttg 1430 tgtgccaaga tatattgtat gtttcatacc ctcaggacctgatctgtaag gaataggccc 1490 tattatgcaa aatgtgaatt tatgtgttat ttatactgacaacttttcaa gcaagaatgt 1550 atcattttta tgacaaccag tgagcacaca atattatgatgccagcacca taatatattt 1610 gtgatggatg ggaacacaga ggtagttaaa tagagacatggagacacgaa tccatttgag 1670 aagtttctgg agacggagat gttagatcct gtatccataaagacttcctt gcggtggtgt 1730 tgataaagca attcagggcc acttgcattt ttaagcaagtttagtttttg gatgcctgaa 1790 tttagaaaga cctgagacaa ataactcaaa ttgagattcagcttcagcca ccttgccagt 1850 ccccatcccc atctatctgt aagtcattgg agagtgacccagggacactg taagtgtctg 1910 gaagtaaaaa ggtcttatga tccaagaggg agaaccaacatggccaagca caaaaaattg 1970 tcagaatttc cagctgctcc ttaatagcca ggcaaaaaaagcacatggat gcaaagaaaa 2030 tggtcaagaa ttgcttactg gacagcgcaa gtgaacctgactggtggatg tgaccagaaa 2090 gtgccaatcg ctgaggtgct acttttaagt aatgaatgtgctttctgtaa agtgatttca 2150 tttcttttct gtttacttat ttgtttttgc attctgacaatgcactaata aaaatataac 2210 tcttgtttgc aataataaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaa 2267 108 329 PRT Canis familiaris 108 Met His Pro GlnGln Leu Val Ile Ser Trp Phe Ser Leu Val Leu Leu 1 5 10 15 Ala Ser ProLeu Met Ala Ile Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu LeuAsp Trp His Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys HisThr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Ala Gln 50 55 60 Ser Ser GluVal Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu PheGly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Lys Val 85 90 95 Leu SerArg Ser Leu Leu Leu Ile His Lys Lys Glu Asp Gly Ile Trp 100 105 110 SerThr Asp Ile Leu Lys Glu Gln Lys Glu Ser Lys Asn Lys Ile Phe 115 120 125Leu Lys Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135140 Leu Thr Ala Ile Ser Thr Asp Leu Lys Phe Ser Val Lys Ser Ser Arg 145150 155 160 Gly Phe Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Val Thr LeuSer 165 170 175 Ala Glu Arg Val Arg Val Asp Asn Arg Asp Tyr Lys Lys TyrThr Val 180 185 190 Glu Cys Gln Glu Gly Ser Ala Cys Pro Ser Ala Glu GluSer Leu Pro 195 200 205 Ile Glu Val Val Val Asp Ala Ile His Lys Leu LysTyr Glu Asn Tyr 210 215 220 Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile LysPro Asp Pro Pro Thr 225 230 235 240 Asn Leu Gln Leu Lys Pro Leu Lys AsnSer Arg His Val Glu Val Ser 245 250 255 Trp Glu Tyr Pro Asp Thr Trp SerThr Pro His Ser Tyr Phe Ser Leu 260 265 270 Thr Phe Cys Ile Gln Ala GlnGly Lys Asn Asn Arg Glu Lys Lys Asp 275 280 285 Arg Leu Cys Val Asp LysThr Ser Ala Lys Val Val Cys His Lys Asp 290 295 300 Ala Lys Ile Arg ValGln Ala Arg Asp Arg Tyr Tyr Ser Ser Ser Trp 305 310 315 320 Ser Asp TrpAla Ser Val Ser Cys Ser 325 109 2267 DNA Canis familiaris 109 tttttttttttttttttttt tttttttttt tttttttttt tattattgca aacaagagtt 60 atatttttattagtgcattg tcagaatgca aaaacaaata agtaaacaga aaagaaatga 120 aatcactttacagaaagcac attcattact taaaagtagc acctcagcga ttggcacttt 180 ctggtcacatccaccagtca ggttcacttg cgctgtccag taagcaattc ttgaccattt 240 tctttgcatccatgtgcttt ttttgcctgg ctattaagga gcagctggaa attctgacaa 300 ttttttgtgcttggccatgt tggttctccc tcttggatca taagaccttt ttacttccag 360 acacttacagtgtccctggg tcactctcca atgacttaca gatagatggg gatggggact 420 ggcaaggtggctgaagctga atctcaattt gagttatttg tctcaggtct ttctaaattc 480 aggcatccaaaaactaaact tgcttaaaaa tgcaagtggc cctgaattgc tttatcaaca 540 ccaccgcaaggaagtcttta tggatacagg atctaacatc tccgtctcca gaaacttctc 600 aaatggattcgtgtctccat gtctctattt aactacctct gtgttcccat ccatcacaaa 660 tatattatggtgctggcatc ataatattgt gtgctcactg gttgtcataa aaatgataca 720 ttcttgcttgaaaagttgtc agtataaata acacataaat tcacattttg cataataggg 780 cctattccttacagatcagg tcctgagggt atgaaacata caatatatct tggcacacaa 840 gtgttcaataacaataaatt aataaataca taaattactt aaatatttaa atagcattaa 900 ggtcagtggcagcctgctag ctgaaaatct ataaataaag tagctgattg tttcagtggg 960 catttggcatttaaatgtaa aaaatattgc gaagacacaa taatgaccct ttacaaaaag 1020 aaaattaggcagaaaataac ttttggagcc tcttcaatgt gtccttagaa aattttgcat 1080 aatatcttccactttccctc caagattcat cctgggggtg gaacctaact gcaggacaca 1140 gatgcccagtcgctccagga tgaactatag tagcggtctc gggcttgcac gcggatcttg 1200 gcatccttgtggcacacgac cttggctgag gtcttgtcca cgcagagtct atctttcttt 1260 tctctattgttcttgccctg ggcctgtatg caaaatgtca gggagaagta ggaatgtggg 1320 gtgctccaggtgtcggggta ttcccagctg acctccacgt gccgagaatt tttcaatggc 1380 ttcagctgcaggtttgtggg tgggtctggt ttgatgatgt ctctgatgaa gaagctgctg 1440 gtgtagttttcatacttgag cttgtgaata gcatccacca cgacctcgat gggtaggctc 1500 tcctcggcagaggggcaggc actgccctcc tgacactcca ctgtgtactt cttataatcc 1560 ctgttgtccactctgaccct ctctgctgaa agtgtcactg ctccacatgt caccccttgg 1620 gggtcagagaagcctctgct acttttgaca ctgaatttca aatcagtact gattgccgtc 1680 agccaccagcatgtgaaacg tccagaataa ttctttgcct cacatttcag aaagatctta 1740 tttttggattctttctgttc ctttaagata tcagtggacc aaattccatc ttcttttttg 1800 tgaatcaacaggagtgagcg gctcagaacc ttgcctcctt tatggcaggt atactggcca 1860 gcatctccaaattctttgac ttggatggtc agagttttac cagaacctag gacttcactg 1920 ctctgcgctgaggtccaagt gatgtcatct tcttcagggg tatggcaggt gaggaccacc 1980 atttctccgggggcatcagg gtgccagtcc aactctacaa cataaacatc tttctccagt 2040 tcccatatggccatgagggg agacgccagc aaaacgaggg aaaaccagga gatgaccaac 2100 tgctgaggatgcatcttgct tctggccagg ctgcaaggtt ccctgggtct gaaacggagt 2160 ctcctgctgctgctgctact gctactggag cttatatacc ctactcctac cgagcttttg 2220 gatggaaacttaaactagaa actgacttgt ccaagttgcc tcgtgcc 2267 110 7 PRT ArtificialSynthetic Linker 110 Gly Gly Gly Gly Gly Gly Ser 1 5 111 10 PRT Feliscatus 111 Arg Asn Leu Pro Thr Pro Thr Pro Ser Pro 1 5 10

1-21 (Canceled)
 22. An isolated nucleic acid molecule selected from thegroup consisting of: (a) an isolated nucleic acid molecule comprising:(i) a nucleic acid sequence encoding a feline p35 subunit protein; (ii)a nucleic acid linker of (XXX)_(n) wherein n=0 to 60; and (iii) anucleic acid sequence encoding a feline p40 subunit protein; and (b) anisolated nucleic acid molecule comprising a nucleic acid sequence fullycomplementary to the nucleic acid molecule set forth in (a).
 23. Theisolated nucleic acid molecule of claim 22, wherein said isolatednucleic acid molecule is selected from the group consisting of: (a) anisolated nucleic acid molecule comprising a feline p35 subunit encodingsequence and a feline p40 subunit encoding sequence, wherein said p35subunit encoding nucleic acid sequence comprises at least 44 contiguousnucleotides identical in sequence to at least 44 contiguous nucleotidesof a nucleic acid sequence selected from the group consisting of SEQ IDNO:32, SEQ ID NO:35 and SEQ ID NO:101; and (b) an isolated nucleic acidmolecule comprising a feline p35 subunit encoding sequence and a felinep40 subunit encoding sequence, wherein said p40 subunit encoding nucleicacid sequence comprises at least 44 contiguous nucleotides identical insequence to at least 44 contiguous nucleotides of a nucleic acidsequence selected from the group consisting of SEQ ID NO:26, SEQ IDNO:29 and SEQ ID NO:55.
 24. The isolated nucleic acid molecule of claim22, wherein said isolated nucleic acid molecule is selected from thegroup consisting of: (a) an isolated nucleic acid molecule comprising afeline p35 subunit encoding sequence and a feline p40 subunit encodingsequence, wherein said p35 subunit encoding nucleic acid sequencecomprises a nucleotide sequence at least 90% identical to SEQ ID NO:32,SEQ ID NO:35 and SEQ ID NO:101; (b) an isolated nucleic acid moleculecomprising a feline p35 subunit encoding sequence and a feline p40subunit encoding sequence, wherein said p40 subunit encoding nucleicacid sequence comprises a nucleotide sequence at least 90% identical toSEQ ID NO:26, SEQ ID NO:29 and SEQ ID NO:55; and (c) an isolated nucleicacid molecule comprising a feline p35 subunit encoding sequence and afeline p40 subunit encoding sequence, wherein said nucleic acid moleculecomprises a nucleic acid sequence at least about 90% identical to SEQ IDNO:38 or SEQ ID NO:43.
 25. The isolated nucleic acid of claim 24,wherein said nucleic acid molecule encodes a protein having a functionselected from the group consisting of: (a) eliciting an immune responseagainst an IL-12 protein having the amino acid sequence of SEQ ID NO:38or SEQ ID NO:43; (b) selectively binding to an antibody raised againstan IL-12 protein having the amino acid sequence of SEQ ID NO:38 or SEQID NO:43; and (c) exhibiting IL-12 activity.
 26. The isolated nucleicacid molecule of claim 22, wherein said nucleic acid linker comprisesSEQ ID NO:83.
 27. The isolated nucleic acid molecule of claim 22,wherein said isolated nucleic acid molecule is selected from the groupconsisting of: (a) an isolated nucleic acid molecule comprising a felinep35 subunit encoding sequence and a feline p40 subunit encodingsequence, wherein said p35 subunit encoding nucleic acid sequencecomprises SEQ ID NO:32, SEQ ID NO:35 or SEQ ID NO:101; (b) an isolatednucleic acid molecule comprising a feline p35 subunit encoding sequenceand a feline p40 subunit encoding sequence, wherein said p40 subunitencoding nucleic acid sequence comprises SEQ ID NO:26, SEQ ID NO:29 orSEQ ID NO:55; and (c) an isolated nucleic acid molecule comprising afeline p35 subunit encoding sequence and a feline p40 subunit encodingsequence, wherein said isolated nucleic acid sequence molecule comprisesSEQ ID NO:38 or SEQ ID NO:43.
 28. The isolated nucleic acid molecule ofclaim 22, wherein said isolated nucleic acid molecule is selected fromthe group consisting of: (a) an isolated nucleic acid moleculecomprising a feline p35 subunit encoding sequence and a feline p40subunit encoding sequence, wherein said p35 subunit encoding nucleicacid sequence consists of SEQ ID NO:32, SEQ ID NO:35 or SEQ ID NO:101;(b) an isolated nucleic acid molecule comprising a feline p35 subunitencoding sequence and a feline p40 subunit encoding sequence, whereinsaid p40 subunit encoding nucleic acid sequence consists of SEQ IDNO:26, SEQ ID NO:29 or SEQ ID NO:55; and (c) an isolated nucleic acidmolecule comprising a feline p35 subunit encoding sequence and a felinep40 subunit encoding sequence, wherein said isolated nucleic acidsequence molecule has a nucleic acid sequences consisting of SEQ IDNO:38 or SEQ ID NO:43.
 29. An isolated nucleic acid molecule selectedfrom the group consisting of: (a) an isolated nucleic acid moleculecomprising: (i) a first nucleic acid sequence encoding a proteincomprising an at least 23 contiguous amino acid region identical insequence to an at least 23 contiguous amino acid region from SEQ IDNO:33, SEQ ID NO:36 or SEQ ID NO:102; (ii) a nucleic acid linker of(XXX)_(n) wherein n=0 to 60; and (iii) a second nucleic acid sequenceencoding a protein comprising an at least 23 contiguous amino acidregion identical in sequence to an at least 23 contiguous amino acidregion from SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:56; and (b) anisolated nucleic acid molecule comprising a nucleic acid sequence fullycomplementary to the nucleic acid molecule set forth in (a).
 30. Theisolated nucleic acid molecule of claim 29, wherein said isolatednucleic acid molecule is selected from the group consisting of: (a) anisolated nucleic acid molecule comprising a first and second nucleicacid sequence, wherein said first nucleic acid sequence encodes aprotein comprising an amino acid sequence at least 90% identical to SEQID NO:33, SEQ ID NO:36 or SEQ ID NO:102; (b) an isolated nucleic acidmolecule comprising a first and second nucleic acid sequence, whereinsaid second nucleic acid sequence encodes a protein comprising an aminoacid sequence at least 90% identical to SEQ ID NO:27, SEQ ID NO:30 orSEQ ID NO:56; and (c) an isolated nucleic acid molecule encoding aprotein comprising an amino acid sequence at least 90% identical to SEQID NO:39 or SEQ ID NO:44.
 31. The isolated nucleic acid of claim 30,wherein said nucleic acid molecule encodes a protein having a functionselected from the group consisting of: (a) eliciting an immune responseagainst an IL-12 protein having the amino acid sequence of SEQ ID NO:27,SEQ ID NO:30 or SEQ ID NO:56; (b) selectively binding to an antibodyraised against an IL-12 protein having the amino acid sequence of SEQ IDNO:27, SEQ ID NO:30 or SEQ ID NO:56; and (c) exhibiting IL-12 activity.32. The isolated nucleic acid molecule of claim 29, wherein saidisolated nucleic acid molecule is selected from the group consisting of:(a) an isolated nucleic acid molecule comprising a first and secondnucleic acid sequence, wherein said first nucleic acid sequence encodesan amino acid sequence comprising SEQ ID NO:33, SEQ ID NO:36 or SEQ IDNO:102; (b) an isolated nucleic acid molecule comprising a first andsecond nucleic acid sequence, wherein said second nucleic acid sequenceencodes an amino acid sequence comprising SEQ ID NO:27, SEQ ID NO:30 orSEQ ID NO:56; and (c) an isolated nucleic acid molecule comprising afirst and second nucleic acid sequence, wherein said isolated nucleicacid sequence encodes a protein comprising SEQ ID NO:39 or SEQ ID NO:44.33. The isolated nucleic acid molecule of claim 29, wherein saidisolated nucleic acid molecule is selected from the group consisting of:(a) an isolated nucleic acid molecule comprising a first and secondnucleic acid sequence, wherein said first nucleic acid sequence encodesan amino acid sequence consisting of SEQ ID NO:33, SEQ ID NO:36 or SEQID NO:102; (b) an isolated nucleic acid molecule comprising a first andsecond nucleic acid sequence, wherein said second nucleic acid sequenceencodes an amino acid sequence consisting of SEQ ID NO:27, SEQ ID NO:30or SEQ ID NO:56; and (c) an isolated nucleic acid molecule comprising afirst and second nucleic acid sequence, wherein said isolated nucleicacid sequence encodes a protein having the sequence of SEQ ID NO:39 orSEQ ID NO:44.
 34. The isolated nucleic acid molecule of claim 29,wherein said nucleic acid linker comprises SEQ ID NO:83.
 35. An isolatedprotein comprising: (a) a feline p35 subunit amino acid sequence; (b) alinker amino acid sequence; and (c) a feline p40 subunit amino acidsequence wherein said linker amino acid sequence links the p35 and p40subunits.
 36. The isolated protein of claim 35, wherein said protein isselected from the group consisting of: (a) an isolated proteincomprising a feline p35 subunit amino acid sequence and a feline p40subunit amino acid sequence, wherein said p35 subunit amino acidsequence comprises an at least 23 contiguous amino acid region identicalin sequence to an at least 23 contiguous amino acid region from SEQ IDNO:33, SEQ ID NO:36 or SEQ ID NO:102; and (b) an isolated proteincomprising a feline p35 subunit amino acid sequence and a feline p40subunit amino acid sequence, wherein said p40 subunit amino acidsequence comprises an at least 23 contiguous amino acid region identicalin sequence to an at least 23 contiguous amino acid region from SEQ IDNO:27, SEQ ID NO:30 or SEQ ID NO:56.
 37. The isolated protein of claim35, wherein said protein is selected from the group consisting of: (a)an isolated protein comprising a feline p35 subunit amino acid sequenceand a feline p40 subunit amino acid sequence, wherein said p35 subunitamino acid sequence comprises an amino acid sequence at least 90%identical to SEQ ID NO:33, SEQ ID NO:36 or SEQ ID NO:102; (b) anisolated protein comprising a feline p35 subunit amino acid sequence anda feline p40 subunit amino acid sequence, wherein said p40 subunit aminoacid sequence comprises an amino acid region at least 90% identical toSEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:56; and (c) an isolated proteincomprising a feline p35 subunit amino acid sequence and a feline p40subunit amino acid sequence, wherein said protein comprises an aminoacid region at least 90% identical to SEQ ID NO:38 or SEQ ID NO:43. 38.The isolated protein of claim 37, wherein said protein has a functionselected from the group consisting of: (a) eliciting an immune responseagainst an IL-12 protein having the amino acid sequence of SEQ ID NO:27,SEQ ID NO:30 or SEQ ID NO:56; (b) selectively binding to an antibodyraised against an IL-12 protein having the amino acid sequence of SEQ IDNO:27, SEQ ID NO:30 or SEQ ID NO:56; and (c) exhibiting IL-12 activity.39. The isolated protein of claim 35, wherein said protein is selectedfrom the group consisting of: (a) an isolated protein comprising afeline p35 subunit amino acid sequence and a feline p40 subunit aminoacid sequence, wherein said p35 subunit amino acid sequence comprisesSEQ ID NO:33, SEQ ID NO:36 or SEQ ID NO:102; (b) an isolated proteincomprising a feline p35 subunit amino acid sequence and a feline p40subunit amino acid sequence, wherein said p40 subunit amino acidsequence comprises SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:56; and (c)an isolated protein comprising a feline p35 subunit amino acid sequenceand a feline p40 subunit amino acid sequence, wherein said proteincomprises the sequence of SEQ ID NO:38 or SEQ ID NO:43.
 40. The isolatedprotein of claim 35, wherein said protein is selected from the groupconsisting of: (a) an isolated protein comprising a feline p35 subunitamino acid sequence and a feline p40 subunit amino acid sequence,wherein said p35 subunit amino acid sequence consists of SEQ ID NO:33,SEQ ID NO:36 or SEQ ID NO:102; (b) an isolated protein comprising afeline p35 subunit amino acid sequence and a feline p40 subunit aminoacid sequence, wherein said p40 subunit amino acid sequence consists ofSEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:56; and (c) an isolated proteincomprising a feline p35 subunit amino acid sequence and a feline p40subunit amino acid sequence, wherein said protein has a sequenceconsisting of SEQ ID NO:38 or SEQ ID NO:43.
 41. The isolated protein ofclaim 35, wherein said protein is encoded by a nucleic acid moleculecomprising a nucleic acid linker sequence, wherein said nucleic acidlinker sequence comprises SEQ ID NO:83.